Substituted 2,3-dihydroimidazo[1,2-c]quinazoline-containing combinations

ABSTRACT

The present invention relates to combinations of: component A: one or more 2,3-dihydroimidazo[1,2-c]quinazoline compounds of general formula (A1) or (A2), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; component B: one or more substituted 5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine compounds of general formula (B), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; in which optionally some or all of the components are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially, dependently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route; use of such combinations for the preparation of a medicament for the treatment or prophylaxis of a cancer; a kit comprising such a combination; use of biomarkers which is the loss of tumor suppressor PTEN or FBXW7, for predicting the sensitivity and/or resistance of a cancer patient to said compound and providing a rationale-based dosage to increase sensitivity and/or to overcome resistance; a method of determining the loss of tumor suppressor PTEN or FBXW7; and a method for determining perturbations in PIK3CA, PIK3CB, PIK3CD, PIK3CG, PI K3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3 and/or FGFR4.

The present invention relates:

to combinations of:

component A: one or more 2,3-dihydroimidazo[1,2-c]quinazoline compoundsof general formula (A1) or (A2), or a physiologically acceptable salt,solvate, hydrate or stereoisomer thereof;

component B: one or more substituted5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine compoundsof general formula (B), or a physiologically acceptable salt, solvate,hydrate or stereoisomer thereof; and, optionally,

component C: one or more further pharmaceutical agents;

in which optionally either or both of components A and B in any of theabove-mentioned combinations are in the form of a pharmaceuticalformulation which is ready for use to be administered simultaneously,concurrently, separately or sequentially. The components may beadministered independently of one another by the oral, intravenous,topical, local installations, intraperitoneal or nasal route.

Another aspect of the present invention relates to the use of suchcombinations as described supra for the preparation of a medicament forthe treatment or prophylaxis of a cancer, particularly endometrialcancer (hereinafter abbreviated to “EC”), particularly 1st line, 2ndline, relapsed, refractory, type I or type II EC, or endometriosis.

Further, the present invention relates to:

a kit comprising:

a combination of:

component A: one or more 2,3-dihydroimidazo[1,2-c]quinazoline compoundsof general formula (A1) or (A2), or a physiologically acceptable salt,solvate, hydrate or stereoisomer thereof;

component B: one or more substituted5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine compoundsof general formula (B), or a physiologically acceptable salt, solvate,hydrate or stereoisomer thereof;

in which optionally either or both of said components (A) and (B) in anyof the above-mentioned combinations are in the form of a pharmaceuticalformulation which is ready for use to be administered simultaneously,concurrently, separately or sequentially. The components may beadministered independently of one another by the oral, intravenous,topical, local installations, intraperitoneal or nasal route.

Further, the present invention relates to:

-   -   use of biomarkers, such as the loss of tumor suppressor PTEN or        FBXW7, either alone or in combination with another form of PI3K        pathway activation selected from perturbation of any of the        following alone or in combination: mutation in PIK3CA, PIK3CB,        PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1,        FGFR2, FGFR3 and/or FGFR4; PTEN-loss and alteration of PIK3CA,        PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5,        FGFR1, FGFR2, FGFR3 and/or FGFR4 which may be measured at either        the protein level, mRNA level, or DNA level,

for predicting the sensitivity and/or resistance of a patient withendometrial cancer (hereinafter abbreviated to “EC”), particularly 1stline, 2nd line, relapsed, refractory, type I or type II EC, orendometriosis, to a combination of a component A and a component B asdefined herein, thus providing rationale-based dosage as defined hereinto overcome said resistance of a patient with endometrial cancer(hereinafter abbreviated to “EC”), particularly 1st line, 2nd line,relapsed, refractory, type I or type II EC, or endometriosis, to acombination of a component A and a component B as defined herein(patient stratification);

a method of determining the loss of tumor suppressor PTEN or FBXW7; and

a method for determining perturbations in PIK3CA, PIK3CB, PIK3CD,PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3and/or FGFR4. PTEN loss and alteration of PIK3CA, PIK3CB, PIK3CD,PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3and/or FGFR4.

BACKGROUND OF THE INVENTION

Cancer is a complex disease arising after a selection process for cellswith acquired functional capabilities like enhanced survival/resistancetowards apoptosis and a limitless proliferative potential. Thus, it ispreferred to develop drugs for cancer therapy addressing distinctfeatures of established tumors.

The PI3K signaling pathway is one of the prominent pathways that promotetumor cell survival. PI3K is activated by many cancer related receptortyrosine kinases (e.g. PDGFR, EGFR, HER2/3, or IGF-1R), cell adhesionmolecules, GPCR, and oncogenic proteins (such as Ras). The PI3K pathwayactivation by genetic alteration of PI3K (activation mutation and/oramplification) and/or loss-of-function of the tumour suppressor PTEN arefrequently found in many tumors. Furthermore, activation of PI3K is oneof the major mechanisms causing the resistance of tumors to radio-,chemo- and targeted therapeutics.

Once PI3K is activated, it catalyzes the generation of PIP3 from PIP2.The biological active PIP3 binds to the pleckstrin homology (PH) domainsof PDK-1, AKT, and other PH-domain containing proteins, such as Rho andPLC. As the consequence of binding to PIP3, these proteins aretranslocated to the cell membrane and are subsequently activated toinduce tumor cell proliferation, survival, invasion and migration.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) drivecrucial developmental signaling pathways, which are responsible for manyfunctions of the tumor cells, including cell proliferation, survival andmigration through downstream signaling pathways mediated by PLCγ/PKC,RAS/MAPK, PI3K/AKT, and STATs. FGFR signaling pathways also regulatetumor stromal cells as well as tumor angiogenesis. There are severaltypes of genetic evidence that support an oncogenic function of FGFRs:gene amplifications, activating mutations, chromosomal translocationsand aberrant splicing at the post-transcriptional level.

Endometrial cancer (EC) is the most common gynecologic malignancy inindustrialized countries, with an incidence rate of 12.9 per 100,000women per year. Early-stage EC (stage I or II) can be effectivelytreated with surgery, while treatment of recurrent or high grademetastatic disease is limited to cytotoxic chemotherapy, e.g. paclitaxeland carboplatin. In addition, for recurrent EC, there are still noagreement and no definitive drugs of choice in spite of the poorprognosis of this subset of patients. It is noteworthy that theavailable chemotherapies do not provide long-term disease control, andmany patients demonstrate intrinsic resistance and significanttoxicities to these therapies. As such, it remains an important unmetmedical need for recurrent EC. The successful management of thesepatients depends on the identification and understanding of molecularmechanisms underlying the initiation and progression of EC to achieve amore tailored therapy, based on the biological tumor profile.

As described in the present text, the anti-tumor efficacy of the PI3Kinhibitor copanlisib was investigated in preclinical tumor models invitro and in vivo in combination. The combination of the PI3K inhibitorcopanlisib with FGFR inhibitors was found to be synergistic, which ledto tumor regression in preclinical tumor model in vivo compared to tumorprogression or tumor stasis in animals treated with monotherapy of eachagent.

Unexpectedly, and this represents a basis of the present invention, whencombinations of:

-   -   component A: a 2,3-dihydroimidazo[1,2-c]quinazoline compound of        general formula (A1) or (A2), or a physiologically acceptable        salt, solvate, hydrate or stereoisomer thereof, as described and        defined herein; with    -   component B: a substituted        5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine        compounds of general formula (B), or a physiologically        acceptable salt, solvate, hydrate or stereoisomer thereof, as        described and defined herein;

were evaluated for the treatment of endometrial cancer (hereinafterabbreviated to “EC”), particularly 1st line, 2nd line, relapsed,refractory, type I or type II EC, or endometriosis, synergisticallyincreased anti-tumor activities were demonstrated with thesecombinations compared to each monotherapy, providing a fundamentalrationale for the clinical combination therapy using PI3Kinhibitors-FGFR inhibitors.

To the Applicant's knowledge, no generic or specific disclosure orsuggestion in the prior art is known that either combinations of:

component A: one or more 2,3-dihydroimidazo[1,2-c]quinazoline compoundsof general formula (A1) or (A2), or a physiologically acceptable salt,solvate, hydrate or stereoisomer thereof;

component B: one or more substituted5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine compoundsof general formula (B), or a physiologically acceptable salt, solvate,hydrate or stereoisomer thereof;

in which optionally either or both of said components A and B of any ofthe above-mentioned combinations are in the form of a pharmaceuticalformulation which is ready for use to be administered simultaneously,concurrently, separately or sequentially, would be effective in thetreatment or prophylaxis of cancer, particularly endometrial cancer(hereinafter abbreviated to “EC”), particularly 1st line, 2nd line,relapsed, refractory, type I or type II EC, or endometriosis.

Based on the action of the testing compounds described in thisinvention, the combinations of the present invention as described anddefined herein, show a beneficial effect in the treatment of cancer,particularly endometrial cancer (hereinafter abbreviated to “EC”),particularly 1st line, 2nd line, relapsed, refractory, type I or type IIEC, or endometriosis.

Accordingly, in accordance with a first aspect, the present inventionrelates: to combinations of:

component A: one or more 2,3-dihydroimidazo[1,2-c]quinazoline compoundsof general formula (A1) or (A2), or a physiologically acceptable salt,solvate, hydrate or stereoisomer thereof;

component B: one or more substituted5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine compoundsof general formula (B), or a physiologically acceptable salt, solvate,hydrate or stereoisomer thereof;

in which optionally either or both of said components A and B) of any ofthe above-mentioned combinations are in the form of a pharmaceuticalformulation which is ready for use to be administered simultaneously,concurrently, separately or sequentially. The components may beadministered independently of one another by the oral, intravenous,topical, local installations, intraperitoneal or nasal route.

In accordance with a second aspect, of the present invention relates tothe use of any of such combinations as described supra for thepreparation of a medicament for the treatment or prophylaxis of acancer, particularly endometrial cancer (hereinafter abbreviated to“EC”), particularly 1st line, 2nd line, relapsed, refractory, type I ortype II EC, or endometriosis.

Further, in accordance with a third aspect, the present inventionrelates to a kit comprising:

a combination of:

component A: one or more 2,3-dihydroimidazo[1,2-c]quinazoline compoundsof general formula (A1) or (A2), or a physiologically acceptable salt,solvate, hydrate or stereoisomer thereof;

component B: one or more substituted5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine compoundsof general formula (B), or a physiologically acceptable salt, solvate,hydrate or stereoisomer thereof;

in which optionally either or both of components A and B in any of theabove-mentioned combinations are in the form of a pharmaceuticalformulation which is ready for use to be administered simultaneously,concurrently, separately or sequentially. The components may beadministered independently of one another by the oral, intravenous,topical, local installations, intraperitoneal or nasal route.

Further, in accordance with a fourth aspect, the present inventionrelates:

-   -   to use of biomarkers, such as the loss of tumor suppressor PTEN        or FBXW7, either alone or in combination with another form of        PI3K pathway activation selected from perturbation of any of the        following alone or in combination: mutation in PIK3CA, PIK3CB,        PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1,        FGFR2, FGFR3 and/or FGFR4; PTEN-loss and alteration of PIK3CA,        PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5,        FGFR1, FGFR2, FGFR3 and/or FGFR4 which may be measured at either        the protein level, mRNA level, or DNA level,

for predicting the sensitivity and/or resistance of a patient withendometrial cancer (hereinafter abbreviated to “EC”), particularly 1stline, 2nd line, relapsed, refractory, type I or type II EC, orendometriosis, to a combination of a component A and a component B asdefined herein, thus providing rationale-based dosage as defined hereinto overcome said resistance of a patient with endometrial cancer(hereinafter abbreviated to “EC”), particularly 1st line, 2nd line,relapsed, refractory, type I or type II EC, or endometriosis, to acombination of a component A and a component B as defined herein(patient stratification);

to a method of determining the loss of tumor suppressor PTEN or FBXW7;and

to a method for determining perturbations in PIK3CA, PIK3CB, PIK3CD,PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3and/or FGFR4. PTEN loss and alteration of PIK3CA, PIK3CB, PIK3CD,PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3and/or FGFR4.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with an embodiment of the above-mentioned aspects of thepresent invention, said combinations are of:

component A: which is one or more 2,3-dihydroimidazo[1,2-c]quinazolinecompounds of general formula (A1):

wherein

X represents CR⁵R⁶ or NH;

Y¹ represents CR³ or N;

Chemical bond between

represents a single bond or double bond,

with the proviso that when the

represents a double bond,

Y² and Y³ independently represent CR⁴ or N, and

when

represents a single bond, Y² and Y³ independently represent CR³R⁴ orNR⁴;

Z¹, Z², Z³ and Z⁴ independently represent CH , CR² or N;

-   -   R¹ represents aryl optionally having 1 to 3 substituents        selected from R¹¹, C₃₋₈ cycloalkyl optionally having 1 to 3        substituents selected from R¹¹,        -   C₁₋₆ alkyl optionally substituted by aryl, heteroaryl, C₁₋₆            alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,        -   C₁₋₆ alkoxy optionally substituted by carboxy, aryl,            heteroaryl, C₁₋₆ alkoxyaryl, aryloxy, heteroaryloxy or one            or more halogen,        -   or        -   a 3 to 15 membered mono- or bi-cyclic heterocyclic ring that            is saturated or unsaturated, and contains 1 to 3 heteroatoms            selected from the group consisting of N, O and S, and            optionally having 1 to 3 substituents selected from R¹¹        -   wherein        -   R¹¹ represents        -   halogen, nitro, hydroxy, cyano, carboxy, amino,            N—(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)amino,            N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆acyl)amino,            N-(formyl)-N—(C₁₋₆alkyl)amino, N—(C₁₋₆alkanesulfonyl) amino,            N-(carboxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino,            N—(C₁₋₆alkoxycabonyl)amino, N—[N,N-di(C₁₋₆alkyl)amino            methylene]amino, N—[N,N-di(C₁₋₆alkyl)amino (C₁₋₆            alkyl)methylene]amino, N-[N,N-di(C₁₋₆alkyl)amino            C₂₋₆alkenyl]amino, aminocarbonyl,            N—(C₁₋₆alkyl)aminocarbonyl, N,N-di(C₁₋₆alkyl)aminocarbonyl,            C₃₋₈cycloalkyl, C₁₋₆alkylthio, C₁₋₆alkanesulfonyl,            sulfamoyl, C₁₋₆alkoxycarbonyl,        -   N-arylamino wherein said aryl moiety is optionally having 1            to 3 substituents selected from R¹⁰¹, N-(aryl            C₁₋₆alkyl)amino wherein said aryl moiety is optionally            having 1 to 3 substituents selected from R¹⁰¹, aryl            C₁₋₆alkoxycarbonyl wherein said aryl moiety is optionally            having 1 to 3 substituents selected from R¹⁰¹,        -   C₁₋₆alkyl optionally substituted by mono-, di- or            tri-halogen, amino, N—(C₁₋₆alkyl)amino or            N,N-di(C₁₋₆alkyl)amino,        -   C₁₋₆alkoxy optionally substituted by mono-, di- or            tri-halogen, N—(C₁₋₆alkyl)sulfonamide, or            N-(aryl)sulfonamide,        -   or        -   a 5 to 7 membered saturated or unsaturated ring having 1 to            3 heteroatoms selected from the group consisting of O, S and            N, and optionally having 1 to 3 substituents selected from            R¹⁰¹        -   wherein        -   R¹⁰¹ represents        -   halogen, carboxy, amino, N—(C₁₋₆ alkyl)amino,            N,N-di(C₁₋₆alkyl)amino, aminocarbonyl,            N—(C₁₋₆alkyl)aminocarbonyl, N,N-di(C₁₋₆alkyl)aminocarbonyl,            pyridyl,        -   C₁₋₆ alkyl optionally substituted by cyano or mono- di- or            tri-halogen,        -   or        -   C₁₋₆alkoxy optionally substituted by cyano, carboxy, amino,            N—(C₁₋₆ alkyl)amino, N,N-di(C₁₋₆alkyl)amino, aminocarbonyl,            N—(C₁₋₆alkyl)aminocarbonyl, N,N-di(C₁₋₆alkyl)aminocarbonyl            or mono-, di- or tri-halogen;    -   R² represents hydroxy, halogen, nitro, cyano, amino,        N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,        N-(hydroxyC₁₋₆alkyl)amino,        N-(hydroxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino, C₁₋₆ acyloxy,        aminoC₁₋₆acyloxy, C₂₋₆alkenyl, aryl,        -   a 5-7 membered saturated or unsaturated heterocyclic ring            having 1 to 3 hetero-atoms selected from the group            consisting O, S and N, and optionally substituted by        -   hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, oxo, amino, amino            C₁₋₆alkyl, N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,            N—(C₁₋₆ acyl)amino, N—(C₁₋₆alkyl)carbonylamino, phenyl,            phenyl C₁₋₆ alkyl, carboxy, C₁₋₆alkoxycarbonyl,            aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl, or            N,N-di(C₁₋₆alkyl)amino,        -   —C(O)—R²⁰        -   wherein        -   R²⁰ represents C₁₋₆ alkyl, C₁₋₆ alkoxy, amino,            N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆            acyl)amino, or a 5-7 membered saturated or unsaturated            heterocyclic ring having 1 to 3 heteroatoms selected from            the group consisting O, S and N, and optionally substituted            by C₁₋₆ alkyl, C₁₋₆ alkoxy, oxo, amino, N—(C₁₋₆alkyl)amino,            N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, phenyl, or            benzyl,        -   C₁₋₆ alkyl optionally substituted by R²¹        -   or        -   C₁₋₆ alkoxy optionally substituted by R²¹        -   wherein        -   R²¹ represents cyano, mono-, di or tri-halogen, hydroxy,            amino, N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,            N-(hydroxyC₁₋₆ alkyl) amino, N-(halophenylC₁₋₆ alkyl) amino,            amino C₂₋₆ alkylenyl, C₁₋₆ alkoxy, hydroxyC₁₋₆ alkoxy,            —C(O)—R²⁰¹, —NHC(O)—R²⁰¹, C₃₋₈cycloalkyl, isoindolino,            phthalimidyl, 2-oxo-1,3-oxazolidinyl, aryl or a 5 or 6            membered saturated or unsaturated heterocyclic ring having 1            to 4 heteroatoms selected from the group consisting O, S and            N optionally substituted by hydroxy, C₁₋₆ alkyl, C₁₋₆            alkoxy, C₁₋₆ alkoxycarbonyl, hydroxyC₁₋₆ alkoxy, oxo, amino,            aminoC₁₋₆alkyl, N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,            N—(C₁₋₆ acyl)amino, or benzyl,            -   wherein            -   R²⁰¹ represents hydroxy, amino, N—(C₁₋₆alkyl)amino,                N,N-di(C₁₋₆alkyl)amino, N-(halophenylC₁₋₆ alkyl) amino,                C₁₋₆alkyl, aminoC₁₋₆ alkyl, aminoC₂₋₆ alkylenyl, C₁₋₆                alkoxy, a 5 or 6 membered saturated or unsaturated                heterocyclic ring having 1 to 4 heteroatoms selected                from the group consisting O, S and N optionally                substituted by hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆                alkoxycarbonyl, hydroxyC₁₋₆ alkoxy, oxo, amino,                N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆                acyl)amino or benzyl;        -   R³ represents hydrogen, halogen, aminocarbonyl, or C₁₋₆            alkyl optionally substituted by aryl C₁₋₆ alkoxy or mono-,            di- or tri-halogen;        -   R⁴ represents hydrogen or C₁₋₆ alkyl;        -   R⁵ represents hydrogen or C₁₋₆ alkyl; and

R⁶ represents halogen, hydrogen or C₁₋₆ alkyl;

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; said compounds are published as compounds of general formulaeI, I-a, and I-b in International patent application PCT/EP2003/010377,published as WO 04/029055 A1 on Apr. 8, 2004, which is incorporatedherein by reference in its entirety. In WO 04/029055, said compounds ofgeneral formula I, I-a and I-b are described on pp. 6 et seq., they maybe synthesized according to the methods given therein on pp. 26 et seq.,and are exemplified as specific compound Examples 1-1 to 1-210 on pp. 47to 106, specific compound Examples 2-1 to 2-368 on pp. 107 to 204,specific compound Examples 3-1 to 3-2 on pp. 205 to 207, and as specificcompound Examples 4-1 to 4-2 on pp. 208 to 210, therein.

Said component A may be in the form of a pharmaceutical formulationwhich is ready for use to be administered simultaneously, concurrently,separately or sequentially. The components may be administeredindependently of one another by the oral, intravenous, topical, localinstallations, intraperitoneal or nasal route.

In accordance with another embodiment of the above-mentioned aspects ofthe present invention, said combinations are of:

component A: which is one or more 2,3-dihydroimidazo[1,2-c]quinazolinecompounds of general formula (A1), supra, which is selected from thelist consisting of specific compound Examples 1-1 to 1-210 on pp. 47 to106, specific compound Examples 2-1 to 2-368 on pp. 107 to 204, specificcompound Examples 3-1 to 3-2 on pp. 205 to 207, and specific compoundExamples 4-1 to 4-2 on pp. 208 to 210, of in International patentapplication PCT/EP2003/010377, published as WO 04/029055 A1 on Apr. 8,2004, which is incorporated herein by reference in its entirety,

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof.

Said component A may be in the form of a pharmaceutical formulationwhich is ready for use to be administered simultaneously, concurrently,separately or sequentially. The components may be administeredindependently of one another by the oral, intravenous, topical, localinstallations, intraperitoneal or nasal route.

As mentioned supra, said specific compound Examples may be synthesizedaccording to the methods given in WO 04/029055 A1 on pp. 26 et seq.

In accordance with another embodiment of the above-mentioned aspects ofthe present invention, said combinations are of:

component A: which is one or more 2,3-dihydroimidazo[1,2-c]quinazolinecompounds of general formula (A2):

in which:

X represents CR⁵R⁶ or NH;

Y¹ represents CR³ or N;

the chemical bond between

represents a single bond or double bond, with the proviso that when the

represents a double bond, Y² and Y³ independently represent CR⁴ or N,and

when

represents a single bond, Y² and Y³ independently represent CR³R⁴ orNR⁴;

Z¹, Z², Z³ and Z⁴ independently represent CH , CR² or N;

-   -   R¹ represents aryl optionally having 1 to 3 substituents        selected from R¹¹, C₃₋₈ cycloalkyl optionally having 1 to 3        substituents selected from R¹¹, C₁₋₆ alkyl optionally        substituted by aryl, heteroaryl, C₁₋₆ alkoxyaryl, aryloxy,        heteroaryloxy or one or more halogen,        -   C₁₋₆ alkoxy optionally substituted by carboxy, aryl,            heteroaryl, C₁₋₆ alkoxyaryl, aryloxy, heteroaryloxy or one            or more halogen,        -   or        -   a 3 to 15 membered mono- or bi-cyclic heterocyclic ring that            is saturated or unsaturated, optionally having 1 to 3            substituents selected from R¹¹, and contains 1 to 3            heteroatoms selected from the group consisting of N, O and            S,        -   wherein        -   R¹¹ represents halogen, nitro, hydroxy, cyano, carboxy,            amino, N—(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)amino,            N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆acyl)amino,            N-(formyl)-N—(C₁₋₆alkyl)amino, N—(C₁₋₆alkanesulfonyl) amino,            N-(carboxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino,            N—(C₁₋₆alkoxycabonyl)amino, N-[N,N-di(C₁₋₆alkyl)amino            methylene]amino, N—[N,N-di(C₁₋₆alkyl)amino            (C₁₋₆alkyl)methylene]amino, N—[N,N-di(C₁₋₆alkyl)amino            C₂₋₆alkenyl]amino, aminocarbonyl,            N—(C₁₋₆alkyl)aminocarbonyl, N,N-di(C₁₋₆alkyl)aminocarbonyl,            C₃₋₈cycloalkyl, C₁₋₆ alkylthio, C₁₋₆alkanesulfonyl,            sulfamoyl, C₁₋₆alkoxycarbonyl,        -   N-arylamino wherein said aryl moiety is optionally having 1            to 3 substituents selected from R¹⁰¹, N-(aryl            C₁₋₆alkyl)amino wherein said aryl moiety is optionally            having 1 to 3 substituents selected from R¹⁰¹, aryl            C₁₋₆alkoxycarbonyl wherein said aryl moiety is optionally            having 1 to 3 substituents selected from R¹⁰¹,        -   C₁₋₆alkyl optionally substituted by mono-, di- or            tri-halogen, amino, N—(C₁₋₆alkyl)amino or            N,N-di(C₁₋₆alkyl)amino,        -   C₁₋₆alkoxy optionally substituted by mono-, di- or            tri-halogen, N—(C₁₋₆alkyl)sulfonamide, or            N-(aryl)sulfonamide,        -   or        -   a 5 to 7 membered saturated or unsaturated ring having 1 to            3 heteroatoms selected from the group consisting of O, S and            N, and optionally having 1 to 3 substituents selected from            R¹⁰¹        -   wherein        -   R¹⁰¹ represents halogen, carboxy, amino, N—(C₁₋₆            alkyl)amino, N,N-di(C₁₋₆alkyl)amino, aminocarbonyl,            N—(C₁₋₆alkyl)aminocarbonyl, N,N-di(C₁₋₆alkyl)aminocarbonyl,            pyridyl,            -   C₁₋₆ alkyl optionally substituted by cyano or mono- di-                or tri-halogen,            -   and            -   C₁₋₆alkoxy optionally substituted by cyano, carboxy,                amino, N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,                aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl,                N,N-di(C₁₋₆alkyl)aminocarbonyl or mono-, di- or                tri-halogen;    -   R² represents hydroxy, halogen, nitro, cyano, amino,        N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,        N-(hydroxyC₁₋₆alkyl)amino,        N-(hydroxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino, C₁₋₆ acyloxy,        aminoC₁₋₆acyloxy, C₂₋₆alkenyl, aryl, a 5-7 membered saturated or        unsaturated heterocyclic ring having 1 to 3 heteroatoms selected        from the group consisting O, S and N, and optionally substituted        by        -   hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, oxo, amino, amino            C₁₋₆alkyl, N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,            N—(C₁₋₆ acyl)amino, N—(C₁₋₆alkyl)carbonylamino, phenyl,            phenyl C₁₋₆ alkyl, carboxy, C₁₋₆alkoxycarbonyl,            aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl, or            N,N-di(C₁₋₆alkyl)amino, —C(O)—R²⁰        -   wherein        -   R²⁰ represents C₁₋₆ alkyl, C₁₋₆ alkoxy, amino,            N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆            acyl)amino, or a 5-7 membered saturated or unsaturated            heterocyclic ring having 1 to 3 heteroatoms selected from            the group consisting O, S and N, and optionally substituted            by C₁₋₆ alkyl, C₁₋₆ alkoxy, oxo, amino, N—(C₁₋₆alkyl)amino,            N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, phenyl, or            benzyl,            -   C₁₋₆ alkyl optionally substituted by R²¹,            -   or            -   C₁₋₆ alkoxy optionally substituted by R²¹, wherein            -   R²¹ represents cyano, mono-, di or tri-halogen, hydroxy,                amino, N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,                N-(hydroxyC₁₋₆ alkyl) amino, N-(halophenylC₁₋₆ alkyl)                amino, amino C₂₋₆ alkylenyl, C₁₋₆ alkoxy, hydroxyC₁₋₆                alkoxy, —C(O)—R²⁰¹, —NHC(O)—R²⁰¹, C₃₋₈cycloalkyl,                isoindolino, phthalimidyl, 2-oxo-1,3-oxazolidinyl, aryl                or a 5 or 6 having 1 to 4 heteroatoms selected from the                group consisting O, S and N , and optionally substituted                by hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆                alkoxycarbonyl, hydroxyC₁₋₆ alkoxy, oxo, amino,                aminoC₁₋₆alkyl, N—(C₁₋₆alkyl)amino,                N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, or benzyl,                -   wherein                -   R²⁰¹ represents hydroxy, amino, N—(C₁₋₆alkyl)amino,                    N,N-di(C₁₋₆alkyl)amino, N-(halophenylC₁₋₆ alkyl)                    amino, C₁₋₆alkyl, aminoC₁₋₆ alkyl, aminoC₂₋₆                    alkylenyl, C₁₋₆ alkoxy, a 5 or 6 membered saturated                    or unsaturated heterocyclic ring having 1 to 4                    heteroatoms selected from the group consisting O, S                    and N, and optionally substituted by hydroxy, C₁₋₆                    alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, hydroxyC₁₋₆                    alkoxy, oxo, amino, N—(C₁₋₆alkyl)amino,                    N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino or                    benzyl;    -   R³ represents hydrogen, halogen, aminocarbonyl, or C₁₋₆ alkyl        optionally substituted by aryl C₁₋₆ alkoxy or mono-, di- or        tri-halogen;    -   R⁴ represents hydrogen or C₁₋₆ alkyl;    -   R⁵ represents hydrogen or C₁₋₆ alkyl; and    -   R⁶ represents halogen, hydrogen or C₁₋₆ alkyl;

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; said compounds are published as compounds of general formulaeI, la, Ib, Ic, Id and le in International patent applicationPCT/US2007/024985, published as WO 2008/070150 A1 on Jun. 12, 2008,which is incorporated herein by reference in its entirety. In WO2008/070150, said compounds of general formula I, Ia, Ib, Ic, Id and Ieare described on pp. 9 et seq., they may be synthesized according to themethods given therein on pp. 42, et seq., and are exemplified asspecific compound Examples 1 to 103 therein on pp. 65 to 101. Biologicaltest data for certain of said compounds are given therein on pp. 101 to107.

The definitions used in relation to the structure (A) in this text areas follows:

The term ‘alkyl’ refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containingsolely of carbon and hydrogen atoms, containing no unsaturation, havingfrom one to eight carbon atoms, and which is attached to the rest of themolecule by a single bond, such as illustratively, methyl, ethyl,n-propyl 1-methylethyl (isopropyl), n-butyl, n-pentyl, and1,1-dimethylethyl (t-butyl).

The term “alkenyl ” refers to an aliphatic hydrocarbon group containinga carbon-carbon double bond and which may be a straight or branched orbranched chain having about 2 to about 10 carbon atoms, e.g., ethenyl,1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl,1-butenyl, 2-and butenyl.

The term “alkynyl” refers to a straight or branched chain hydrocarbonylradicals having at least one carbon-carbon triple bond, and having inthe range of about 2 up to 12 carbon atoms (with radicals having in therange of about 2 up to 10 carbon atoms presently being preferred) e.g.,ethynyl.

The term “alkoxy” denotes an alkyl group as defined herein attached viaoxygen linkage to the rest of the molecule. Representative examples ofthose groups are methoxy and ethoxy.

The term “alkoxyakyl” denotes an alkoxy group as defined herein attachedvia oxygen linkage to an alkyl group which is then attached to the mainstructure at any carbon from alkyl group that results in the creation ofa stable structure the rest of the molecule. Representative examples ofthose groups are —CH₂OCH₃, —CH₂OC₂H₅.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and examples of multicyclic cycloalkyl groupsinclude perhydronapththyl, adamantyl and norbornyl groups bridged cyclicgroup or sprirobicyclic groups e.g spiro (4,4) non-2-yl.

The term “cycloalkylalkyl” refers to cyclic ring-containing radicalscontaining in the range of about about 3 up to 8 carbon atoms directlyattached to alkyl group which is then also attached to the mainstructure at any carbon from the alkyl group that results in thecreation of a stable structure such as cyclopropylmethyl,cyclobutylethyl, cyclopentylethyl.

The term “aryl” refers to aromatic radicals having in the range of 6 upto 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl,biphenyl.

The term “arylalkyl” refers to an aryl group as defined herein directlybonded to an alkyl group as defined herein which is then attached to themain structure at any carbon from alkyl group that results in thecreation of a stable structure the rest of the molecule. e.g., —CH₂C₆H₅,—C₂H₅C₆H₅.

The term “heterocyclic ring” refers to a stable 3- to 15 membered ringradical which consists of carbon atoms and from one to five heteroatomsselected from the group consisting of nitrogen, phosphorus, oxygen andsulfur. For purposes of this invention, the heterocyclic ring radicalmay be a monocyclic, bicyclic or tricyclic ring system, which mayinclude fused, bridged or spiro ring systems, and the nitrogen,phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ringradical may be optionally oxidized to various oxidation states. Inaddition, the nitrogen atom may be optionally quaternized; and the ringradical may be partially or fully saturated (i.e., heteroaromatic orheteroaryl aromatic). Examples of such heterocyclic ring radicalsinclude, but are not limited to, azetidinyl, acridinyl, benzodioxolyl,benzodioxanyl, benzofurnyl, carbazolyl cinnolinyl dioxolanyl,indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazil, pyridyl, pteridinyl, purinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,imidazolyl tetrahydroisouinolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinylpyridazinyl, oxazolyl oxazolinyl oxasolidinyl, triazolyl, indanyl,isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,isoindolyl, indolinyl, isoindolinyl, octahydroindolyl,octahydroisoindolyl quinolyl, isoquinolyl, decahydroisoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl,benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl,benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide thiamorpholinylsulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, isochromanyl.

The term “heteroaryl” refers to heterocyclic ring radical as definedherein which are aromatic. The heteroaryl ring radical may be attachedto the main structure at any heteroatom or carbon atom that results inthe creation of a stable structure.

The heterocyclic ring radical may be attached to the main structure atany heteroatom or carbon atom that results in the creation of a stablestructure.

The term “heteroarylalkyl” refers to heteroaryl ring radical as definedherein directly bonded to alkyl group. The heteroarylalkyl radical maybe attached to the main structure at any carbon atom from alkyl groupthat results in the creation of a stable structure.

The term “heterocyclyl” refers to a heterocylic ring radical as definedherein. The heterocylyl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure.

The term “heterocyclylalkyl” refers to a heterocylic ring radical asdefined herein directly bonded to alkyl group. The heterocyclylalkylradical may be attached to the main structure at carbon atom in thealkyl group that results in the creation of a stable structure.

The term “carbonyl” refers to an oxygen atom bound to a carbon atom ofthe molecule by a double bond.

The term “halogen” refers to radicals of fluorine, chlorine, bromine andiodine.

Said component A may be in the form of a pharmaceutical formulationwhich is ready for use to be administered simultaneously, concurrently,separately or sequentially. The components may be administeredindependently of one another by the oral, intravenous, topical, localinstallations, intraperitoneal or nasal route.

In accordance with another embodiment of the above-mentioned aspects ofthe present invention, said combinations are of:

component A: which is one or more 2,3-dihydroimidazo[1,2-c]quinazolinecompounds of general formula (A2), supra, which is selected from thelist consisting of:

EXAMPLE 1N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamideEXAMPLE 2N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamideEXAMPLE 3N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-2,4-dimethyl-1,3-thiazole-5-carboxamideEXAMPLE 42-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-thiazole-5-carboxamide.EXAMPLE 52-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]isonicotinamideEXAMPLE 62-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-methyl-1,3-thiazole-5-carboxamideEXAMPLE 72-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-propylpyrimidine-5-carboxamideEXAMPLE 8N-{8-[2-(4-ethylmorpholin-2-yl)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamideEXAMPLE 9N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamideEXAMPLE 10N-(8-{8-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamideEXAMPLE 11N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamideEXAMPLE 12N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide1-oxide EXAMPLE 132-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide.EXAMPLE 14N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(2-pyrrolidin-1-ylethyl)nicotinamide.EXAMPLE 156-(cyclopentylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide

1

Example Structure 16

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103 

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, said compounds are published as specific compound Examples 1 to103 in International patent application PCT/US2007/024985, published asWO 2008/070150 A1 on Jun. 12, 2008, which is incorporated herein byreference in its entirety. In WO 2008/070150, said specific compoundExamples may be synthesized according to the Examples. Biological testdata for certain of said compounds are given therein on pp. 101 to 107.

Said component A may be in the form of a pharmaceutical formulationwhich is ready for use to be administered simultaneously, concurrently,separately or sequentially. The components may be administeredindependently of one another by the oral, intravenous, topical, localinstallations, intraperitoneal or nasal route.

In accordance with an embodiment of the above-mentioned aspects of thepresent invention, said combinations are of:

component B: which is one or more substituted5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine compoundsof general formula (B):

-   -   wherein    -   R¹ is hydrogen, chloro, methyl or methoxy,    -   R² is hydrogen or methoxy, with the proviso that at least one of        R¹ and R² is other than hydrogen,    -   G¹ represents chloro, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxycarbonyl,        5-membered aza-heteroaryl, or the group —CH₂—OR³, —CH₂—NR⁴R⁵ or        —C(═O)—NR⁴R⁶, wherein        -   R³ is hydrogen, (C₁-C₄)-alkyl, (C₃-C₆)-cycloalkyl or phenyl,            -   (i) said (C₁-C₄)-alkyl is optionally substituted with                hydroxy, (C₁-C₄)-alkoxy, hydroxycarbonyl,                (C₁-C₄)-alkoxycarbonyl, amino, aminocarbonyl,                mono-(C₁-C₄)-alkylaminocarbonyl,                di-(C₁-C₄)-alkylaminocarbonyl, (C₃-C₆)-cycloalkyl or up                to three fluoro atoms,            -   and            -   (ii) said (C₃-C₆)-cycloalkyl is optionally substituted                with one or two substituents independently selected from                the group consisting of (C₁-C₄)-alkyl, hydroxy and                amino,            -   and            -   (iii) said phenyl is optionally substituted with one or                two substituents independently selected from the group                consisting of fluoro, chloro, bromo, cyano,                trifluoromethyl, trifluoromethoxy, (C₁-C₄)-alkyl and                (C₁-C₄)-alkoxy,        -   R⁴ is hydrogen or (C₁-C₄)-alkyl,        -   R⁵ is hydrogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkylcarbonyl,            (C₃-C₆)-cycloalkyl or 4- to 6-membered heterocycloalkyl,            wherein            -   (i) said (C₁-C₄)-alkyl is optionally substituted with                hydroxy, (C₁-C₄)-alkoxy, hydroxycarbonyl,                (C₁-C₄)-alkoxycarbonyl, amino-carbonyl,                mono-(C₁-C₄)-alkylaminocarbonyl,                di-(C₁-C₄)-alkylaminocarbonyl or (C₃-C₆)-cycloalkyl,            -   and            -   (ii) said (C₃-C₆)-cycloalkyl is optionally substituted                with one or two substituents independently selected from                the group consisting of (C₁-C₄)-alkyl, hydroxy and                amino,            -   and            -   (iii) said 4- to 6-membered heterocycloalkyl is                optionally substituted with one or two substituents                independently selected from the group consisting of                (C₁-C₄)-alkyl, hydroxy, oxo and amino,        -   R⁶ is hydrogen, (C₁-C₄)-alkyl, (C₃-C₆)-cycloalkyl or 4- to            6-membered heterocycloalkyl, wherein            -   (i) said (C₁-C₄)-alkyl is optionally substituted with                hydroxy, (C₁-C₄)-alkoxy, hydroxycarbonyl,                (C₁-C₄)-alkoxycarbonyl, amino, aminocarbonyl,                mono-(C₁-C₄)-alkylaminocarbonyl,                di-(C₁-C₄)-alkylaminocarbonyl or (C₃-C₆)-cycloalkyl,            -   and            -   (ii) said (C₃-C₆)-cycloalkyl is optionally substituted                with one or two substituents independently selected from                the group consisting of (C₁-C₄)-alkyl, hydroxy and                amino,            -   and            -   (iii) said 4- to 6-membered heterocycloalkyl is                optionally substituted with one or two substituents                independently selected from the group consisting of                (C₁-C₄)-alkyl, hydroxy, oxo and amino,        -   or        -   R⁴ and R⁵, or R⁴ and R⁶, respectively, are joined and, taken            together with the nitrogen atom to which they are attached,            form a monocyclic, saturated 4- to 7-membered            heterocycloalkyl ring which may contain a second ring            heteroatom selected from N(R⁷) and O, and which may be            substituted on ring carbon atoms with one or two            substituents independently selected from the group            consisting of (C₁-C₄)-alkyl, oxo, hydroxy, amino and            aminocarbonyl, and wherein            -   R⁷ is hydrogen, (C₁-C₄)-alkyl, formyl or                (C₁-C₄)-alkylcarbonyl,    -   and    -   G² represents chloro, cyano, (C₁-C₄)-alkyl, or the group        —CR^(8A) R ^(8B)—OH, —CH₂—NR⁹R¹⁰, —C(═O)—NR¹¹R¹² or —CH₂—OR¹⁵,        wherein        -   R^(8A) and R^(8B) are independently selected from the group            consisting of hydrogen, (C₁-C₄)-alkyl, cyclopropyl and            cyclobutyl,        -   R⁹ is hydrogen or (C₁-C₄)-alkyl,        -   R¹⁰ is hydrogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkylcarbonyl,            (C₃-C₆)-cycloalkyl or 4- to 6-membered heterocycloalkyl,            wherein            -   (i) said (C₁-C₄)-alkyl is optionally substituted with                hydroxy, amino, aminocarbonyl,                mono-(C₁-C₄)-alkylaminocarbonyl or                di-(C₁-C₄)-alkylaminocarbonyl,            -   and            -   (ii) said (C₃-C₆)-cycloalkyl is optionally substituted                with one or two substituents independently selected from                the group consisting of (C₁-C₄)-alkyl, hydroxy and                amino,            -   and            -   (iii) said 4- to 6-membered heterocycloalkyl is                optionally substituted with one or two substituents                independently selected from the group consisting of                (C₁-C₄)-alkyl, hydroxy, oxo and amino,        -   R¹¹ is hydrogen or (C₁-C₄)-alkyl,        -   R¹² is hydrogen, (C₁-C₄)-alkyl, (C₃-C₆)-cycloalkyl or 4- to            6-membered heterocycloalkyl, wherein            -   (i) said (C₁-C₄)-alkyl is optionally substituted with                hydroxy, amino, aminocarbonyl,                mono-(C₁-C₄)-alkylaminocarbonyl or                di-(C₁-C₄)-alkylaminocarbonyl,            -   and            -   (ii) said (C₃-C₆)-cycloalkyl is optionally substituted                with one or two substituents independently selected from                the group consisting of (C₁-C₄)-alkyl, hydroxy and                amino,            -   and            -   (iii) said 4- to 6-membered heterocycloalkyl is                optionally substituted with one or two substituents                independently selected from the group consisting of                (C₁-C₄)-alkyl, hydroxy, oxo and amino,        -   or        -   R⁹ and R¹⁰, or R¹¹ and R¹², respectively, are joined and,            taken together with the nitrogen atom to which they are            attached, form a monocyclic, saturated 4- to 7-membered            heterocycloalkyl ring which may contain a second ring            heteroatom selected from N(R¹³), O, S and S(O)₂, and which            may be substituted on ring carbon atoms with up to three            substituents independently selected from the group            consisting of fluoro, (C₁-C₄)-alkyl, oxo, hydroxy, amino and            aminocarbonyl, and wherein            -   R¹³ is hydrogen, (C₁-C₄)-alkyl, (C₃-C₆)-cycloalkyl,                formyl or (C₁-C₄)-alkylcarbonyl,        -   and        -   R¹⁵ is (C₁-C₄)-alkyl,    -   with the proviso that G¹ is not chloro when G² is chloro or        cyano,

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof;

said compounds are published as compounds of general formula (I) inInternational patent application PCT/EP2012/074977, published as WO2013/087578 on Jun. 20, 2013, which is incorporated herein by referencein its entirety. In WO 2013/087578, said compounds of general formula(I) are described on pp. 5 et seq., pp. 13 et seq. and pp. 109 et seq.,they may be synthesized according to the methods given therein on pp.19, et seq. and pp. 53 et seq., and are exemplified as specific compoundExamples 1 to 127 therein on pp. 109 to 205. Biological test data forcertain of said compounds are given therein on pp. 206 to 226.

The definitions used in relation to the structure (B) in this text areas follows:

(C₁-C₄)-Alkyl in the context of the invention represents astraight-chain or branched alkyl radical having 1 to 4 carbon atoms.There may be mentioned by way of example and preferably: methyl, ethyl,n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.

(C₁-C₄)-Alkoxy in the context of the invention represents astraight-chain or branched alkoxy radical having 1 to 4 carbon atoms.There may be mentioned by way of example and preferably: methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, andtert-butoxy.

Mono-(C₁-C₄)-alkylamino in the context of the invention represents anamino group with a straight-chain or branched alkyl substituent whichcontains 1 to 4 carbon atoms. There may be mentioned by way of exampleand preferably: methylamino, ethylamino, n-propylamino, isopropylamino,n-butylamino, and tert-butylamino.

Di-(C₁-C₄)-alkylamino in the context of the invention represents anamino group with two identical or different straight-chain or branchedalkyl substituents which each contain 1 to 4 carbon atoms. There may bementioned by way of example and preferably: N,N-dimethylamino,N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-methylamino, N-isopropyl-N-n-propylamino,N,N-diisopropylamino, N-n-butyl-N-methylamino, andN-tert-butyl-N-methylamino.

(C₁-C₄)-Alkylcarbonyl in the context of the invention represents astraight-chain or branched alkyl radical having 1 to 4 carbon atomswhich is bonded to the rest of the molecule via a carbonyl group[—C(═O)—]. There may be mentioned by way of example and preferably:acetyl, propionyl, n-butyryl, iso-butyryl, n-pentanoyl, and pivaloyl.

(C₁-C₄)-Alkoxycarbonyl in the context of the invention represents astraight-chain or branched alkoxy radical having 1 to 4 carbon atomswhich is bonded to the rest of the molecule via a carbonyl group[—C(═O)—]. There may be mentioned by way of example and preferably:methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,n-butoxycarbonyl, and tert-butoxycarbonyl.

Mono-(C₁-C₄)-alkylaminocarbonyl in the context of the inventionrepresents an amino group which is bonded to the rest of the moleculevia a carbonyl group [—C(═O)—] and which has a straight-chain orbranched alkyl substituent having 1 to 4 carbon atoms. There may bementioned by way of example and preferably: methylaminocarbonyl,ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl,n-butylamino-carbonyl, and tert-butylaminocarbonyl.

Di-(C₁-C₄)-alkylaminocarbonyl in the context of the invention representsan amino group which is bonded to the rest of the molecule via acarbonyl group [—C(═O)—] and which has two identical or differentstraight-chain or branched alkyl substituents having in each case 1 to 4carbon atoms. There may be mentioned by way of example and preferably:N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl,N-ethyl-N-methyl-aminocarbonyl, N-methyl-N-n-propylaminocarbonyl,N-isopropyl-N-methylamino-carbonyl, N,N-diisopropylaminocarbonyl,N-n-butyl-N-methylaminocarbonyl, and N-tert-butyl-N-methylaminocarbonyl.

(C₃-C₆)-Cycloalkyl in the context of the invention represents amonocyclic, saturated carbocycle having 3 to 6 ring carbon atoms. Theremay be mentioned by way of example: cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. Preferred are cyclopropyl and cyclobutyl.

4- to 7-membered heterocycloalkyl and 4- to 6-membered heterocycloalkylin the context of the invention represent a monocyclic, saturatedheterocycle with 4 to 7 or, respectively, 4 to 6 ring atoms in total,which contains one or two identical or different ring heteroatoms fromthe series N, O, S and S(O)₂, and which can be bonded via a ring carbonatom or via a ring nitrogen atom (if present). 4- to 6-memberedheterocycloalkyl containing one ring nitrogen atom and optionally onefurther ring heteroatom from the series N, O or S(O)₂ is preferred. 5-or 6-membered heterocycloalkyl containing one ring nitrogen atom andoptionally one further ring heteroatom from the series N or O isparticularly preferred. There may be mentioned by way of example:azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl,imidazolidinyl, tetrahydrofuranyl, thiolanyl, 1,1-dioxidothiolanyl,1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl, piperidinyl,piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl,1,4-dioxanyl, 1,2-oxazinanyl, morpholinyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl, azepanyl, 1,4-diazepanyl, and1,4-oxazepanyl. Preferred are azetidinyl, pyrrolidinyl, pyrazolidinyl,imidazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, piperidinyl,piperazinyl, 1,2-oxazinanyl, morpholinyl, and thiomorpholinyl.Particularly preferred are pyrrolidinyl, piperidinyl, piperazinyl, andmorpholinyl.

5-membered aza-heteroaryl in the context of the invention represents anaromatic heterocyclic radical (heteroaromatic) having 5 ring atoms intotal, which contains at least one ring nitrogen atom and optionally oneor two further ring heteroatoms from the series N, O and/or S, and whichis bonded via a ring carbon atom or optionally via a ring nitrogen atom(when allowed by valency). 5-membered aza-heteroaryl containing one ringnitrogen atom and one or two further ring heteroatoms from the series Nand/or O is preferred. There may be mentioned by way of example:pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl. Preferred arepyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and oxadiazolyl. An oxosubstituent in the context of the invention represents an oxygen atom,which is bonded to a carbon atom via a double bond.

Said component B may be in the form of a pharmaceutical formulationwhich is ready for use to be administered simultaneously, concurrently,separately or sequentially. The components may be administeredindependently of one another by the oral, intravenous, topical, localinstallations, intraperitoneal or nasal route.

In accordance with another embodiment of the above-mentioned aspects ofthe present invention, said combinations are of:

component B: which is one or more substituted5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine compoundsof general formula (B), supra, which is selected from the listconsisting of:

EXAMPLE 1

4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-one

EXAMPLE 2

4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-onedihydrochloride

EXAMPLE 3

(3R)-3-({[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-onedihydrochloride

EXAMPLE 4

(3R)-3-({[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-one

EXAMPLE 5

4-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-one

EXAMPLE 6

4-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo-[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-onedihydrochloride

EXAMPLE 7

(3R)-3-({[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-onedihydrochloride

EXAMPLE 8

(3R)-3-({[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-one

EXAMPLE 9

N²-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}glycinamidedihydrochloride

EXAMPLE 10

6-(Ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

EXAMPLE 11

1-(4-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-1-yl)ethanonedihydrochloride

EXAMPLE 12

[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methanolbis(formiate)

EXAMPLE 13

4-{[4-Amino-6-(hydroxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-one

EXAMPLE 14

7-{[(3S)-3-Amino-3-methylpyrrolidin-1-yl]methyl}-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride

EXAMPLE 15

7-{[(3S)-3-Amino-3-methylpyrrolidin-1-yl]methyl}-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

EXAMPLE 16

1-(4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-1-yl)ethanonedihydrochloride

EXAMPLE 17

6-(Methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineformiate

EXAMPLE 18

6-(Ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

EXAMPLE 19

6-(Ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminedihydrochloride

EXAMPLE 20

1-(4-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo-[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-1-yl)ethanone

EXAMPLE 21

4-({4-Amino-6-[(2-hydroxyethoxy)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl}methyl)piperazin-2-oneformiate

EXAMPLE 22

2-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methoxy}ethanoldihydrochloride

EXAMPLE 23

6-(Butoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineformiate

EXAMPLE 24

5-(7-Methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)-6-(propoxy-methyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminebis(formiate)

EXAMPLE 25

6-[(Cyclopropylmethoxy)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminebis(formiate)

EXAMPLE 26

6-[(Cyclobutyloxy)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

EXAMPLE 27

6-(Isopropoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-yl-methyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineformiate

EXAMPLE 28

6-[(2-Methoxyethoxy)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineformiate

EXAMPLE 29

5-(7-Methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)-6-[(2,2,2-trifluoroethoxy)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-amineformiate

EXAMPLE 30

6-[(2-Aminoethoxy)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride

EXAMPLE 31

Methyl{[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-yl-methyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methoxy}acetate

EXAMPLE 32

{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methoxy}aceticacid

EXAMPLE 33

2-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methoxy}acetamide

EXAMPLE 34

2-({7-[(4-Acetylpiperazin-1-yl)methyl]-4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl}methoxy)acetamide

EXAMPLE 35

5-(7-Methoxy-5-methyl-1-benzothiophen-2-yl)-6-(phenoxymethyl)-7-(piperazin-1-yl-methyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminebis(formiate)

EXAMPLE 36

5-(7-Methoxy-5-methyl-1-benzothiophen-2-yl)-6-[(methylamino)methyl]-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride

EXAMPLE 37

6-[(Dimethylamino)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride

EXAMPLE 38

6-[(Ethylamino)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride

EXAMPLE 39

2-({[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}amino)ethanoltrihydrochloride

EXAMPLE 40

rac-1-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperidin-3-oltrihydrochloride

EXAMPLE 41

1-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperidin-4-oltrihydrochloride

EXAMPLE 42

rac-1-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}pyrrolidin-3-oltrihydrochloride

EXAMPLE 43

6-[(Diethylamino)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride

EXAMPLE 44

6-[(Cyclobutylamino)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride

EXAMPLE 45

5-(7-Methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)-6-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride

EXAMPLE 46

6-[(Cyclopropylamino)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride

EXAMPLE 47

6-{[(Cyclopropylmethyl)amino]methyl}-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride

EXAMPLE 48

N-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}glycinetrihydrochloride

EXAMPLE 49

4-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperazin-2-onetrihydrochloride

EXAMPLE 50

[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methanol

EXAMPLE 51

(3S)-3-({[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}amino)pyrrolidin-2-one

EXAMPLE 52

4-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperazin-2-one

EXAMPLE 53

rac-1-({[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}amino)propan-2-ol

EXAMPLE 54

1-({[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}amino)-2-methylpropan-2-ol

EXAMPLE 55

1-(4-{[4-Amino-6-(hydroxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-1-yl)ethanone

EXAMPLE 56

(3R)-3-[({7-[(4-Acetylpiperazin-1-yl)methyl]-4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl}methyl)amino]pyrrolidin-2-one

EXAMPLE 57

1-(4-{[4-Amino-6-{[(2-hydroxy-2-methylpropyl)amino]methyl}-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-1-yl)ethanone

EXAMPLE 58

4-({4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-6-[(3-oxopiperazin-1-yl)-methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}methyl)piperazine-1-carbaldehydeformiate

EXAMPLE 59

4-({7-[(4-Acetylpiperazin-1-yl)methyl]-4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl}methyl)piperazin-2-one

EXAMPLE 60

Methyl4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylcarbonyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylatebis(formiate)

EXAMPLE 61

5-(7-Methoxy-5-methyl-1-benzothiophen-2-yl)-6-(1,3-oxazol-5-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride

EXAMPLE 62

6-(Aminomethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride

EXAMPLE 63

N-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}acetamidebis(trifluoroacetate)

EXAMPLE 64

N-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}acetamidedihydrochloride

EXAMPLE 65

N-({4-Amino-7-[(4-formylpiperazin-1-yl)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl}methyl)acetamideformiate

EXAMPLE 66

N-({7-[(4-Acetylpiperazin-1-yl)methyl]-4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl}methyl)acetamide

EXAMPLE 67

N-({4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl}methyl)acetamide

EXAMPLE 68

4-Amino-6-(hydroxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carbonitrile

EXAMPLE 69

4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carbonitrile

EXAMPLE 70

4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carbonitrile

EXAMPLE 71

4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-6-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazine-7-carbonitrile

EXAMPLE 72

N,N′-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazine-6,7-diyl]bis(methylene)}diacetamide

EXAMPLE 73

2-[4-Amino-6-(hydroxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]propan-2-ol

EXAMPLE 74

4-{[4-Amino-7-(2-hydroxypropan-2-yl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperazin-2-one

EXAMPLE 75

[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]methanol

EXAMPLE 76

4-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperazin-2-one

EXAMPLE 77

1-({[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}amino)-2-methylpropan-2-olformiate

EXAMPLE 78

1-({[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}amino)-2-methylpropan-2-ol

EXAMPLE 79

[4-Amino-7-chloro-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methanol

EXAMPLE 80

4-{[4-Amino-7-chloro-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperazin-2-one

EXAMPLE 81

1-({[4-Amino-7-chloro-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}amino)-2-methylpropan-2-olformiate

EXAMPLE 82

1-({[4-Amino-7-chloro-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}amino)-2-methylpropan-2-ol

EXAMPLE 83

7-Chloro-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f]-[1,2,4]triazin-4-amine

EXAMPLE 84

5-(7-Methoxy-5-methyl-1-benzothiophen-2-yl)-6-methyl-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineformiate

EXAMPLE 85

6-Chloro-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride

EXAMPLE 86

[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methanol

EXAMPLE 87

1-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}imidazolidin-2-one

EXAMPLE 88

4-{[4-Amino-5-(7-methoxy-1-benzothiophen-2-yl)-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-one

EXAMPLE 89

4-{[4-Amino-6-(methoxymethyl)-5-(5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-one

EXAMPLE 90

1-[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]ethanol

EXAMPLE 91

[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl](cyclopropyl)methanol

EXAMPLE 92

(3S)-3-({[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-one

EXAMPLE 93

(3S)-3-({[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-one

Example No. Structure 94

95

96

97

98

99

100

101

102

103

104

105

EXAMPLE 106

4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-N-[(3R)-2-oxopyrrolidin-3-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide

EXAMPLE 107

4-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]carbonyl}piperazin-2-one

Example No. Structure 108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

EXAMPLE 124

4-{[4-Amino-5-(5,7-dimethoxy-1-benzothiophen-2-yl)-6-(methoxymethyl)pyrrolo[2,1-f]-[1,2,4]triazin-7-yl]methyl}piperazin-2-one

EXAMPLE 125

4-{[4-Amino-7-(hydroxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperazin-2-one

EXAMPLE 126

4-{[4-Amino-7-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperazin-2-one

EXAMPLE 127

4-{[4-Amino-7-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperazin-2-one

In accordance with an embodiment of the above-mentioned aspects of thepresent invention, said combinations are of:

component A:2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;and

component B:4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-one.

Said component B may be in the form of a pharmaceutical formulationwhich is ready for use to be administered simultaneously, concurrently,separately or sequentially. The components may be administeredindependently of one another by the oral, intravenous, topical, localinstallations, intraperitoneal or nasal route.

In accordance with an embodiment, the present invention relates to acombination of any component A mentioned herein with any component Bmentioned herein.

In a particular embodiment, the present invention relates to acombination of a component A with a component B, as mentioned in theExamples section herein.

Useful Forms of Components A and B of the Combinations of the PresentInvention

As mentioned supra, either or both of components A and B of any of thecombinations of the present invention may be in a useful form, such aspharmaceutically acceptable salts, co-precipitates, metabolites,hydrates, solvates and prodrugs of all the compounds of examples. Theterm “pharmaceutically acceptable salt” refers to a relativelynon-toxic, inorganic or organic acid addition salt of a compound of thepresent invention. For example, see S. M. Berge, et al. “PharmaceuticalSalts,” J. Pharm. Sci. 1977, 66, 1-19. Pharmaceutically acceptable saltsinclude those obtained by reacting the main compound, functioning as abase, with an inorganic or organic acid to form a salt, for example,salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinicacid and citric acid. Pharmaceutically acceptable salts also includethose in which the main compound functions as an acid and is reactedwith an appropriate base to form, e.g., sodium, potassium, calcium,magnesium, ammonium, and chlorine salts. Those skilled in the art willfurther recognize that acid addition salts of the claimed compounds maybe prepared by reaction of the compounds with the appropriate inorganicor organic acid via any of a number of known methods. Alternatively,alkali and alkaline earth metal salts of acidic compounds of theinvention are prepared by reacting the compounds of the invention withthe appropriate base via a variety of known methods.

Representative salts of the compounds of this invention include theconventional non-toxic salts and the quaternary ammonium salts which areformed, for example, from inorganic or organic acids or bases by meanswell known in the art. For example, such acid addition salts includeacetate, adipate, alginate, ascorbate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide,iodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate,mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate,picrate, pivalate, propionate, succinate, sulfonate, sulfate, tartrate,thiocyanate, tosylate, and undecanoate.

Base salts include alkali metal salts such as potassium and sodiumsalts, alkaline earth metal salts such as calcium and magnesium salts,and ammonium salts with organic bases such as dicyclohexylamine andN-methyl-D-glucamine. Additionally, basic nitrogen containing groups maybe quaternized with such agents as lower alkyl halides such as methyl,ethyl, propyl, or butyl chlorides, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl sulfate, or diamyl sulfates,long chain halides such as decyl, lauryl, myristyl and strearylchlorides, bromides and iodides, aralkyl halides like benzyl andphenethyl bromides and others.

A solvate for the purpose of this invention is a complex of a solventand a compound of the invention in the solid state. Exemplary solvateswould include, but are not limited to, complexes of a compound of theinvention with ethanol or methanol. Hydrates are a specific form ofsolvate wherein the solvent is water.

Pharmaceutical Formulations of Components A and B of the Combinations ofthe Present Invention

As mentioned supra, the components A or B may, independently from oneanother, be in the form of a pharmaceutical formulation which is readyfor use to be administered simultaneously, concurrently, separately orsequentially. The components may be administered independently of oneanother by the oral, intravenous, topical, local installations,intraperitoneal or nasal route.

Said compositions can be utilized to achieve the desired pharmacologicaleffect by administration to a patient in need thereof. A patient, forthe purpose of this invention, is a mammal, including a human, in needof treatment for the particular condition or disease. Therefore, thepresent invention includes combinations in which components A and B,independently of one another, are pharmaceutical formulationscompositions that are comprised of a pharmaceutically acceptable carrierand a pharmaceutically effective amount of a said component. Apharmaceutically acceptable carrier is preferably a carrier that isrelatively non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of component, and/or combination. A pharmaceutically effectiveamount of a combination is preferably that amount which produces aresult or exerts an influence on the particular condition being treated.The combinations of the present invention can be administered withpharmaceutically-acceptable carriers well known in the art using anyeffective conventional dosage unit forms, including immediate, slow andtimed release preparations, orally, parenterally, topically, nasally,ophthalmically, optically, sublingually, rectally, vaginally, and thelike.

For oral administration, the combinations can be formulated into solidor liquid preparations such as capsules, pills, tablets, troches,lozenges, melts, powders, solutions, suspensions, or emulsions, and maybe prepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatin typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the combinations of this invention may betableted with conventional tablet bases such as lactose, sucrose andcornstarch in combination with binders such as acacia, corn starch orgelatin, disintegrating agents intended to assist the break-up anddissolution of the tablet following administration such as potatostarch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia,lubricants intended to improve the flow of tablet granulation and toprevent the adhesion of tablet material to the surfaces of the tabletdies and punches, for example talc, stearic acid, or magnesium, calciumor zinc stearate, dyes, coloring agents, and flavoring agents such aspeppermint, oil of wintergreen, or cherry flavoring, intended to enhancethe aesthetic qualities of the tablets and make them more acceptable tothe patient. Suitable excipients for use in oral liquid dosage formsinclude dicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit.

For instance tablets, pills or capsules may be coated with shellac,sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavoring and coloring agentsdescribed above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavoring and coloring agents.

The combinations of this invention may also be administeredparenterally, that is, subcutaneously, intravenously, intraocularly,intrasynovially, intramuscularly, or interperitoneally, as injectabledosages of the compound in preferably a physiologically acceptablediluent with a pharmaceutical carrier which can be a sterile liquid ormixture of liquids such as water, saline, aqueous dextrose and relatedsugar solutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methycellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid.

Suitable fatty acid esters are, for example, ethyl oleate and isopropylmyristate. Suitable soaps include fatty acid alkali metal, ammonium, andtriethanolamine salts and suitable detergents include cationicdetergents, for example dimethyl dialkyl ammonium halides, alkylpyridinium halides, and alkylamine acetates; anionic detergents, forexample, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, andmonoglyceride sulfates, and sulfosuccinates; non-ionic detergents, forexample, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimize or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB. Illustrative of surfactants used inparenteral formulations are the class of polyethylene sorbitan fattyacid esters, for example, sorbitan monooleate and the high molecularweight adducts of ethylene oxide with a hydrophobic base, formed by thecondensation of propylene oxide with propylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al, “Compendium of Excipients for ParenteralFormulations” PDA Journal of Pharmaceutical Science & Technology 1998,52(5), 238-311; Strickley, R. G “Parenteral Formulations of SmallMolecule Therapeutics Marketed in the United States (1999)-Part-1” PDAJournal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; andNema, S. et al, “Excipients and Their Use in Injectable Products” PDAJournal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);

adsorbents (examples include but are not limited to powdered celluloseand activated charcoal);

aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃)

air displacement agents (examples include but are not limited tonitrogen and argon);

antifungal preservatives (examples include but are not limited tobenzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben,sodium benzoate);

antimicrobial preservatives (examples include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);

antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);

binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyurethanes,silicones, polysiloxanes and styrene-butadiene copolymers);

buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate dihydrate)

carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection)

chelating agents (examples include but are not limited to edetatedisodium and edetic acid)

colorants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel and ferric oxide red);

clarifying agents (examples include but are not limited to bentonite);emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate)

flavorants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);

humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);

levigating agents (examples include but are not limited to mineral oiland glycerin);

oils (examples include but are not limited to arachis oil, mineral oil,olive oil, peanut oil, sesame oil and vegetable oil);

ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);

penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas)

plasticizers (examples include but are not limited to diethyl phthalateand glycerol);

solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation);

stiffening agents (examples include but are not limited to cetylalcohol, cetyl esters wax, microcrystalline wax, paraffin, stearylalcohol, white wax and yellow wax);

suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures));

surfactants (examples include but are not limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);

suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);

sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose);

tablet anti-adherents (examples include but are not limited to magnesiumstearate and talc);

tablet binders (examples include but are not limited to acacia, alginicacid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose,gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);

tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac);

tablet direct compression excipients (examples include but are notlimited to dibasic calcium phosphate);

tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, cross-linked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);

tablet glidants (examples include but are not limited to colloidalsilica, corn starch and talc);

tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);

tablet/capsule opaquants (examples include but are not limited totitanium dioxide);

tablet polishing agents (examples include but are not limited to carnubawax and white wax);

thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);

tonicity agents (examples include but are not limited to dextrose andsodium chloride);

viscosity increasing agents (examples include but are not limited toalginic acid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth);and

wetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile IV Solution: A 5 mg/mL solution of the desired compound of thisinvention can be made using sterile, injectable water, and the pH isadjusted if necessary. The solution is diluted for administration to 1-2mg/mL with sterile 5% dextrose and is administered as an IV infusionover about 60 minutes.

Lyophilized powder for IV administration: A sterile preparation can beprepared with (i) 100-1000 mg of the desired compound of this inventionas a lypholized powder, (ii) 32-327 mg/mL sodium citrate, and (iii)300-3000 mg Dextran 40. The formulation is reconstituted with sterile,injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL,which is further diluted with saline or dextrose 5% to 0.2-0.4 mg/mL,and is administered either IV bolus or by IV infusion over 15-60minutes.

Intramuscular suspension: The following solution or suspension can beprepared, for intramuscular injection:

50 mg/mL of the desired, water-insoluble compound of this invention

5 mg/mL sodium carboxymethylcellulose

4 mg/mL TWEEN 80

9 mg/mL sodium chloride

9 mg/mL benzyl alcohol

Hard Shell Capsules: A large number of unit capsules are prepared byfilling standard two-piece hard galantine capsules each with 100 mg ofpowdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in a digestibleoil such as soybean oil, cottonseed oil or olive oil is prepared andinjected by means of a positive displacement pump into molten gelatin toform soft gelatin capsules containing 100 mg of the active ingredient.The capsules are washed and dried. The active ingredient can bedissolved in a mixture of polyethylene glycol, glycerin and sorbitol toprepare a water miscible medicine mix.

Tablets: A large number of tablets are prepared by conventionalprocedures so that the dosage unit is 100 mg of active ingredient, 0.2mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules: These are solid oral dosage formsmade by conventional and novel processes. These units are taken orallywithout water for immediate dissolution and delivery of the medication.The active ingredient is mixed in a liquid containing ingredient such assugar, gelatin, pectin and sweeteners. These liquids are solidified intosolid tablets or caplets by freeze drying and solid state extractiontechniques. The drug compounds may be compressed with viscoelastic andthermoelastic sugars and polymers or effervescent components to produceporous matrices intended for immediate release, without the need ofwater.

Method of Treating Cancer

Within the context of the present invention, the term “cancer” includes,but is not limited to, cancers of the endometrium, breast, lung, brain,reproductive organs, digestive tract, urinary tract, liver, eye, skin,head and neck, thyroid, parathyroid and their distant metastases. Thosedisorders also include multiple myeloma, lymphomas, sarcomas, andleukemias.

Examples of endometrial cancer include, but not limited to type I EC(estrogen-dependent and/or progesterone-dependent with endometrioidhistology) and type II EC, or endometriosis (hormone-independent poorlydifferentiated endometrioid, clear cell and serous carcinomas).

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumors of the female reproductive organsinclude, but are not limited to endometrial, cervical, ovarian, vaginal,and vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer and squamous cell.

Lymphomas include, but are not limited to AIDS-related lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma,Hodgkin's disease, and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

The present invention relates to a method for using the combinations ofthe present invention, in the treatment or prophylaxis of a cancer,particularly endometrial cancer (hereinafter abbreviated to “EC”),particularly 1st line, 2nd line, relapsed, refractory, type I or type IIEC, or endometriosis. The combinations of the present invention can beutilized to inhibit, block, reduce, decrease, etc., cell proliferationand/or cell division, and/or produce apoptosis, in the treatment orprophylaxis of cancer, in particular EC (hereinafter abbreviated to“EC”), particularly 1st line, 2nd line, relapsed, refractory, type I ortype II EC, or endometriosis. This method comprises administering to amammal in need thereof, including a human, an amount of a combination ofthis invention, or a pharmaceutically acceptable salt, isomer,polymorph, metabolite, hydrate, solvate or ester thereof; etc. which iseffective for the treatment or prophylaxis of cancer, in particular EC,particularly 1st line, 2nd line, relapsed, refractory, type I or type IIEC, or endometriosis.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder, such as a carcinoma.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment or prophylaxis of cancer, in particularendometrial cancer (EC), particularly 1st line, 2nd line, relapsed,refractory, type I or type II EC, or endometriosis, by standard toxicitytests and by standard pharmacological assays for the determination oftreatment of the conditions identified above in mammals, and bycomparison of these results with the results of known medicaments thatare used to treat these conditions, the effective dosage of thecombinations of this invention can readily be determined for treatmentof the indication. The amount of the active ingredient to beadministered in the treatment of the condition can vary widely accordingto such considerations as the particular combination and dosage unitemployed, the mode of administration, the period of treatment, the ageand sex of the patient treated, and the nature and extent of thecondition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1,500 mg of active ingredient, andcan be administered one or more times per day or less than once a day.The average daily dosage for administration by injection, includingintravenous, intramuscular, subcutaneous and parenteral injections, anduse of infusion techniques will preferably be from 0.01 to 200 mg/kg oftotal body weight. The average daily rectal dosage regimen willpreferably be from 0.01 to 200 mg/kg of total body weight. The averagedaily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kgof total body weight. The average daily topical dosage regimen willpreferably be from 0.1 to 200 mg administered between one to four timesdaily. The transdermal concentration will preferably be that required tomaintain a daily dose of from 0.01 to 200 mg/kg. The average dailyinhalation dosage regimen will preferably be from 0.01 to 100 mg/kg oftotal body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific combination employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a combination of the presentinvention or a pharmaceutically acceptable salt or ester or compositionthereof can be ascertained by those skilled in the art usingconventional treatment tests.

Therapies Using Combinations of Component A as Described Supra,Component B as Described Supra, and Component C: One or More FurtherPharmaceutical Agents.

The combinations of component A and component B of this invention can beadministered as the sole pharmaceutical agent or in combination with oneor more further pharmaceutical agents where the resulting combination ofcomponents A, B and C causes no unacceptable adverse effects. Forexample, the combinations of components A and B of this invention can becombined with component C, i.e. one or more further pharmaceuticalagents, such as known anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagents, and the like, as well as with admixtures and combinationsthereof.

Component C, can be one or more pharmaceutical agents such as1311-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumabemtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronicacid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexylaminolevulinate,amrubicin, amsacrine, anastrozole, ancestim, anetholedithiolethione, angiotensin II, antithrombin III, aprepitant,arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib,azacitidine, basiliximab, belotecan, bendamustine, belinostat,bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin,bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan,cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate,capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine,catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil,chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin,cladribine, clodronic acid, clofarabine, crisantaspase,cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin,darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine,degarelix, denileukin diftitox, denosumab, depreotide, deslorelin,dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac,docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin+estrone,dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopag,endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetinalfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib,esomeprazole, estradiol, estramustine, etoposide, everolimus,exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone,floxuridine, fludarabine, fluorouracil, flutamide, folinic acid,formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol,gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid,gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab,Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocytecolony stimulating factor, histamine dihydrochloride, histrelin,hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid,ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib,imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate,interferon alfa, interferon beta, interferon gamma, iobitridol,iobenguane (123I), iomeprol, ipilimumab, irinotecan, Itraconazole,ixabepilone, lanreotide, lapatinib, lasocholine, lenalidomide,lenograstim, lentinan, letrozole, leuprorelin, levamisole,levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine,lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol,melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate,methoxsalen, methylaminolevulinate, methylprednisolone,methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin,mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane,mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphinehydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin,naloxone+pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine,neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide,nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab,octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole,ondansetron, oprelvekin, orgotein, orilotimod, oxaliplatin, oxycodone,oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palifermin,palladium-103 seed, palonosetron, pamidronic acid, panitumumab,pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxyPEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b,pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane,perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin,pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate,polyvinylpyrrolidone+sodium hyaluronate, polysaccharide-K, pomalidomide,ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone,procarbazine, procodazole, propranolol, quinagolide, rabeprazole,racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed,ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronic acid, rhenium-186 etidronate, rituximab,romidepsin, romiplostim, romurtide, roniciclib , samarium (153Sm)lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sizofiran,sobuzoxane, sodium glycididazole, sorafenib, stanozolol, streptozocin,sunitinib, talaporfin, tamibarotene, tamoxifen, tapentadol, tasonermin,teceleukin, technetium (99mTc) nofetumomab merpentan,99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur+gimeracil+oteracil,temoporfin, temozolomide, temsirolimus, teniposide, testosterone,tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa,tioguanine, tocilizumab, topotecan, toremifene, tositumomab,trabectedin, tramadol, trastuzumab, trastuzumab emtansine, treosulfan,tretinoin, trifluridine+tipiracil, trilostane, triptorelin, trametinib,trofosfamide, thrombopoietin, tryptophan, ubenimex, valrubicin,vandetanib, vapreotide, vemurafenib, vinblastine, vincristine,vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole,yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer,zoledronic acid, zorubicin, or combinations thereof.

Alternatively, said component C can be one or more furtherpharmaceutical agents selected from gemcitabine, paclitaxel (whencomponent B is not itself paclitaxel), cisplatin, carboplatin, sodiumbutyrate, 5-FU, doxirubicin, tamoxifen, etoposide, trastumazab,gefitinib, intron A, rapamycin, 17-AAG, U0126, insulin, an insulinderivative, a PPAR ligand, a sulfonylurea drug, an a-glucosidaseinhibitor, a biguanide, a PTP-1B inhibitor, a DPP-IV inhibitor, a11-beta-HSD inhibitor, GLP-1, a GLP-1 derivative, GIP, a GIP derivative,PACAP, a PACAP derivative, secretin or a secretin derivative.

Optional anti-hyper-proliferative agents which can be added as componentC to the combination of components A and B of the present inventioninclude but are not limited to compounds listed on the cancerchemotherapy drug regimens in the 11th Edition of the Merck Index,(1996), which is hereby incorporated by reference, such as asparaginase,bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin,doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil,hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin,lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate,mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine,raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine,vincristine, and vindesine.

Other anti-hyper-proliferative agents suitable for use as component Cwith the combination of components A and B of the present inventioninclude but are not limited to those compounds acknowledged to be usedin the treatment of neoplastic diseases in Goodman and Gilman's ThePharmacological Basis of Therapeutics (Ninth Edition), editor Molinoffet al., publ. by McGraw-Hill, pages 1225-1287, (1996), which is herebyincorporated by reference, such as aminoglutethimide, L-asparaginase,azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol,2′,2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine,ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridinemonophosphate, fludarabine phosphate, fluoxymesterone, flutamide,hydroxyprogesterone caproate, idarubicin, interferon,medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane,paclitaxel (when component B is not itself paclitaxel), pentostatin,N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide,testosterone propionate, thiotepa, trimethylmelamine, uridine, andvinorelbine.

Other anti-hyper-proliferative agents suitable for use as component Cwith the combination of components A and B of the present inventioninclude but are not limited to other anti-cancer agents such asepothilone and its derivatives, irinotecan, raloxifen and topotecan.

Generally, the use of cytotoxic and/or cytostatic agents as component Cin combination with a combination of components A and B of the presentinvention will serve to:

(1) yield better efficacy in reducing the growth of a tumor or eveneliminate the tumor as compared to administration of either agent alone,

(2) provide for the administration of lesser amounts of the administeredchemo-therapeutic agents,

(3) provide for a chemotherapeutic treatment that is well tolerated inthe patient with fewer deleterious pharmacological complications thanobserved with single agent chemotherapies and certain other combinedtherapies,

(4) provide for treating a broader spectrum of different cancer types inmammals, especially humans,

(5) provide for a higher response rate among treated patients,

(6) provide for a longer survival time among treated patients comparedto standard chemotherapy treatments,

(7) provide a longer time for tumor progression, and/or

(8) yield efficacy and tolerability results at least as good as those ofthe agents used alone, compared to known instances where other canceragent combinations produce antagonistic effects.

Biomarkers:

Biomarkers used for patient stratification are e.g. the loss of tumorsuppressor PTEN or FBXW7,

-   -   either alone or in combination with another form of PI3K pathway        activation selected from perturbation of any of the following        alone or in combination: mutation in PIK3CA, PIK3CB, PIK3CD,        PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2,        FGFR3 and/or FGFR4; PTEN loss and alteration of PIK3CA, PIK3CB,        PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1,        FGFR2, FGFR3 and/or FGFR4, which may be measured at either the        protein level, mRNA level, or DNA level,

for predicting the sensitivity and/or resistance of a patient withendometrial cancer (hereinafter abbreviated to “EC”), particularly 1stline, 2nd line, relapsed, refractory, type I or type II EC, orendometriosis, to a combination of a component A and a component B asdefined herein, thus providing rationale-based dosage as defined hereinto overcome said resistance of a patient with endometrial cancer(hereinafter abbreviated to “EC”), particularly 1st line, 2nd line,relapsed, refractory, type I or type II EC, or endometriosis, to acombination of a component A and a component B as defined herein(patient stratification).

EXAMPLES

The following abbreviations are used in the Examples:

Component A:

-   -   “copanlisib” or “compound A” means compound Example 13 of WO        2008/070150 A1 as shown herein (which is an example of component        A as described and defined herein);    -   “copanlisib dihydrochloride” or “compound A*” means compound        Example 1 of European patent application number EP 11 161 111.7,        and in PCT application number PCT/EP2012/055600 published under        WO 2012/136553, both of which are hereby incorporated herein in        their entirety by reference (which is an example of component A        as described and defined herein).

Component B:

-   -   “FGFRi” or “compound B” means compound Example 1 of WO        2013/087578, i.e. a compound of structure:

(which is an example of component B as described and defined herein).

Materials and Methods:

In vitro combination assessment: The effects of combinations of thepresent invention were evaluated using combination index isobologramanalysis for in vitro assessment. The efficacy parameters were theeffects in a 48-hour caspase 3/7 activation assay. Briefly, cells wereplated in 384-well plate with 25 μL medium. After 24 hours, 5 μL ofexperimental media containing:

-   -   either A alone, or    -   B alone, or    -   the combination of A (as component A) plus either B, (as        component B), at different ratios (***) were used to make serial        3-fold dilutions to generate response curves with 7        concentrations. Experiments were conducted in triplicates.        Caspase 3/7 assay was conducted at 48 hours after compound        exposure.

The in vivo efficacy was evaluated in tumor xenograft models in nudemice with established human tumor cell lines at the MTD and sub-MTDdosages. Tumor cells were cultivated according to ATCC protocols inrecommended media contained 10% FCS. Cells were harvested fortransplantation in a subconfluent (70%) state. The number of cells forinoculation was indicated in Table 1. The volume of implantation was 100μl for mice. When the tumors were approximately in size of 25-50 mm²,the animals were randomized to treatment and control groups andtreatment was started. Treatment of each animal was based on individualbody weight. The optimal formulation, application route and schedulewere used for each compound (see table 2). Oral administration (p.o.)was carried out via a gastric tube. The oral application volumes were 10ml/kg and the intravenous application volumes were 10 ml/kg. Tumor area(product of the longest diameter and its perpendicular) using a caliper.The animal body weight was monitored as a measure for treatment-relatedtoxicity. Measurement of tumor area and body weight was performed 2-3times weekly. T/C ratios (Treatment/Control) were calculated with finaltumor areas. Treatment responses were evaluated by means of theclinically-used RECIST criteria (complete response, partial response,stable disease and progressive disease) and response rates werecalculated accordingly (RR=number of animals with complete and partialresponse).

TABLE 1 Tumor models used for assessment of compound A (copanlisib) andcompound B (FGFRi) in endometrial tumor models in vivo. Tumor model Modeof Implantation MFE 280 s.c. implantation of 1 × 10⁶ cells suspended in50% Matrigel into the inguinal region of female mice

TABLE 2 Formulations, application route and schedules used in the invivo studies. Application Application Drug Formulation route scheduleCompound A 5% Mannitol/0.9% NaCl i.v. Q2D Doxorubicin 0.9% NaCl i.p.Q14D Compound B 10% EtOH, 40% Solutol, p.o. QD 50% water (~2% HCl [2M])

The invention is demonstrated in the following examples which are notmeant to limit the invention in any way:

Cell Line IC50 (M) Molecular features Histological Subtype RUCA  1.37E−08 PTEN^(del), ER+ Type I ECC-1   1.61E−7 PTEN^(del),PIK3R1^(mut), ER+, PR+, Ishikawa   3.73E−07 PTEN^(del), PIK3R1^(mut),ER+, PR+ HEC-50   6.46E−08 PIK3R1^(mut), KRAS^(mut) Type II RL95-2  1.44E−07 PIK3R1^(mut)/PTEN^(del)/NF2/BRCA2/ KLE <6.86E−09 FBXW7^(mut)HEC-1B <6.86E−09 PIK3CA^(mut), PIK3R2^(mut), PTEN^(Loss)(protein) andKRAS^(mut) AN3CA <6.86E−09 PTEN^(del), FBXW7, FGFR2^(N549K, K310R)HEC-1A <6.86E−09 PIK3CA^(G1049R), PIK3R2^(mut), KRAS^(mut) MFE 280<6.86E−09 PIK3CA^(G1047Y), RB^(del), FGFR2^(5252W) MFE 296 <6.86E−09PTEN^(del), FGFR2^(N549K), UTX^(del,)

Example 1 Synergistic Combination of PI3K Inhibitor Compound A(Copanlisib) and FGFR Inhibitor Compound B in MFE 280 Endometrial TumorModel

As indicated in Table 1 and in Cosmic database, endometrial cancer is aheterogeneous disease with distinct molecular characteristics. The mostfrequent aberration is the activation of the PI3K and loss-of-functionof PTEN. It has been reported that activating mutations of FGFR2 arepresent in both type I and type II endometrial cancer (Pollock et al).Activating mutations in FGFR2 have been identified in approximately 10%of human endometrial carcinomas. Three out of 11 cell lines tested invitro harbor activating FGFR2 mutation (MFE 280, MFE296 and AN3CA).Surprisingly, these 3 cell lines all have coexisting PIK3CA mutations orloss-of-function of PTEN, but no KRAS mutation.

FIG. 1. Synergistic combination of PI3K inhibitor compound A(Copanlisib) with FGFR inhibitor compound B in MFE-280 cells(PIK3CA^(G1047Y), FGFR2^(S252W)). The combination of PI3K inhibitorcompound A (copanlisib) and FGFR inhibitor compound B was tested andcompared to the single agent activity in MFE 280 to address the activityin apoptosis induction using a cleaved caspase 3/7 assay. MFE 280 cellsare bearing both activating PIK3CA and FGFR2 mutations. As single agent,neither Compound A nor Compound B showed apoptosis induction up to 5 and10 μM, respectively. However when combining Compound A and Compound B,significant apoptosis was induced at sub-μM concentrations, e.g. 0.33 μMof compound A+0.44 μM compound B (FIG. 1. (A)), 0.22 μM compound A+0.66μM compound B (FIG. 1. (B)).

FIG. 2. Synergistic combination of PI3K inhibitor compound A(Copanlisib) with FGFR inhibitor compound B in MFE-296 cells(PTEN^(del), FGFR2^(N549K)). The combination of PI3K inhibitor compoundA (copanlisib) and FGFR inhibitor compound B was tested and compared tothe single agent activity in MFE 296 to address the activity inapoptosis induction using a cleaved caspase 3/7 assay. MFE 296 cells arebearing activating FGFR2 mutation and loss-of-PTEN. As single agent,neither Compound A nor Compound B showed apoptosis induction up to 5 and10 μM, respectively. However when combining Compound A and Compound B,dose-dependent apoptosis was detected by measuring activated caspase3/7.

FIG. 3. Synergistic combination of PI3K inhibitor compound A(Copanlisib) with FGFR inhibitor compound B in MFE-280 xenograft tumormodel. The combination of PI3K inhibitor compound A (copanlisib) andFGFR inhibitor compound B was tested and compared to the single agentactivity and the SoC doxorubicin in MFE 280, an endometrial tumor modelbearing both activating PIK3CA and FGFR2 mutations. At a tumor size ofabout 40 mm² the subcutaneously growing MFE-280 tumors were treatedintravenously with two different doses of compound A (copanlisib), 14(filled triangles)/10 (open triangles) mg/kg, and 7 mg/kg) and incombination of compound A and compound B. The dosing schedule forcompound A is depicted in FIG. 3A with triangles. No body weight losswas observed compared to starting body weight in both monotherapy andcombination therapy with 7 mg/kg of compound A. The dose of compound Aat 14 mg/kg (filled triangles) was reduced to 10 mg/kg (open triangles)in both monotherapy and combination groups due to individual animalshowed body weight loss in the combination group. Doxorubicin wasapplied intravenously 1 time every 14 days as a SoC reference.

Treatment of PI3K inhibitor compound A (copanlisib) led to anapproximately 84% (({4)10 mg/kg) and 76% (7 mg/kg) reduction of tumorweight. FGFR inhibitor compound B also reached 78% tumor growthinhibition at the end of the study. Both inhibitors were more potentcompared to the SoC Doxorubicin (61% tumor growth inhibition assessed bytumor weight). Combination of compound B with ({4)10 mg/kg and 7 mg/kgcompound A (copanlisib) further enhanced tumor growth inhibition to 99%and 96%, respectively. More importantly, combination therapy led to 100%response rate compared to 12.5% to 37.5% response rate in the animalgroups treated with each single agent. Of note, 57% and 25% of theanimals in the combination therapy groups even reached complete tumorremission (Table 3). Furthermore, combination of compound A (copanlisib7 mg/kg) and compound B (FGFRi 75 mg/kg) was well tolerated without bodyweight loss during the entire treatment period, only individual bodyweight loss were observed with compound A (copanlisib 14 mg/kg) andcompound B (FGFRi 75 mg/kg) which triggered reduction of the dose ofcompound A to 10 mk/kg after the fourth treatment doses (FIG. 4).

Example 2 Clinical Benefit of PI3K Inhibitor Compound A (Copanlisib) inEndometrial Cancer Patients

In a phase I dose escalation study, subjects were treated with CompoundA (copanlisib) administered intravenously over 60 minutes on days 1, 8,and 15 of every 28 day cycle. Seventeen subjects were treated in 5 doseescalation cohorts (0.1, 0.2, 0.4, 0.8, and 1.2 mg/kg), and the maximumtolerated dose (MTD) was determined to be 0.8 mg/kg. Additional patientswere enrolled into the study in 3 expansion cohorts treated at the MTDto assess safety, pharmacokinetics, biomarkers, and clinical benefit inselected patient populations, including solid tumors (n=25), non-Hodgkinlymphoma (NHL; n=9), and diabetic solid tumor patients (n=6; treated at0.4 mg/kg). Clinical benefit (patients experiencing complete response[CR], partial response [PR], or stable disease [SD]) was observed in 4of 5 (80%) endometrial cancer patients treated in this study (Table 4),including one patient with CR and 2 with extended SD lasting more than 8cycles (more than 224 days).

PIK3CA, BRAF, and KRAS mutations were tested using digital PCR onarchival tumor samples and cell free DNA isolated from plasma. Nextgeneration sequencing (NGS) of a panel of tumor genes andimmunohistochemistry (IHC) for PTEN protein were also performed onarchival tumor samples. Of note, the sole patient in the study with a CRhad an endometrial cancer with PTEN loss by IHC and mutations in boththe PTEN and PIK3CA genes (Table 4). Of the 2 endometrial cancerpatients with extended SD lasting more than 8 cycles, PTEN data couldonly be generated for 1 (patient #2117), and this tumor was alsoPTEN-negative by IHC (Table 4). The other endometrial cancer patientwith extended SD (with 24.3% tumor shrinkage) harbored a KRAS tumormutation (Table 4). This data shows that Compound A (copanlisib) mayprovide clinical benefit to patients with endometrial cancer either withor without PIK3CA mutations, with or without PTEN loss or mutation, andwith or without mutations in KRAS. Activation of PI3K pathway signalingvia a number of mechanisms alone or in combination, such as PTEN lossand/or mutation, PIK3CA mutation, and/or KRAS mutation, may enrichCompound A (copanlisib) activity in this population.

TABLE 4 Clinical outcomes and biomarker data among endometrial cancerpatients treated in a phase I study of Compound A (copanlisib) Nb PriorBest % PTEN Systemic Stage change in protein Anti-cancer At Compound Atumor size PIK3CA PTEN (IHC, % BRAF KRAS Therapy Study (copanlisib) Bestfrom mutation mutation of cells mutation mutation Pt # (setting) Entrydose response screening status status positive) status status 2004 2 IV0.4 mg/kg SD 8 cycles −24.3 WT Nd nd WT MUT (adjuvant) (40 mg) 2008 2 IV0.8 mg/kg PD 2.4 MUT Nd nd WT WT (adjuvant) (40 mg) (H1047R) 2116 2 IV0.8 mg/kg SD 2 cycles −8.7 WT Nd 25% WT WT (palliative) (59 mg) (PTEN-positive) 2117 2 IIIC 0.8 mg/kg SD 8 cycles −9.1 WT Nd  0% WT WT(adjuvant) (51 mg) (PTEN- negative) 3106 0* IV 0.8 mg/kg CR^(#) −61.8MUT MUT 0% WT WT (adjuvant) (46 mg, then 37 (T1052K/ (PTEN- mg°) R88L)negative) Pt, patient; WT, wild-type; MUT, mutant; nd, not done *Onlysurgery, patient declined adjuvant chemotherapy and radiation ^(#)PR atend of cycle 2 until end of cycle 8, then CR until end of cycle 14 °Dosereduction at cycle 5 due to adverse event

These findings provide a rationale to develop personalized therapies forthe treatment of endometrial cancer (hereinafter abbreviated to “EC”),particularly 1st line, 2nd line, relapsed, refractory, type I or type IIEC, or endometriosis.

Hence, as mentioned supra, the present invention relates to the use ofbiomarkers which is the loss of tumor suppressor PTEN or FBXW7, eitheralone or in combination with another form of PI3K pathway activation (asdescribed in the next paragraph), for predicting the sensitivity and/orresistance of a patient with endometrial cancer (hereinafter abbreviatedto “EC”), particularly 1st line, 2nd line, relapsed, refractory, type Ior type II EC, or endometriosis, to a2,3-dihydroimidazo[1,2-c]quinazoline compound as defined herein, thusproviding rationale-based dosage as defined herein to overcomeresistance (patient selection or stratification). Other forms of PI3Kpathway activation include, but are not limited to, perturbation of anyof the following alone or in combination: mutation in PIK3CA, PIK3CB,PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2,FGFR3 and/or FGFR4. PTEN loss and alteration of PIK3CA, PIK3CB, PIK3CD,PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3and/or FGFR4 may be measured at either the protein level, mRNA level, orDNA level.

In accordance with an embodiment, the present invention relates to amethod of determining the loss of tumor suppressor PTEN or FBXW7.

In accordance with another embodiment, the present invention relates toa method for determining perturbations in PIK3CA, PIK3CB, PIK3CD,PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3and/or FGFR4. PTEN loss and alteration o of PIK3CA, PIK3CB, PIK3CD,PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3and/or FGFR4.

1. A combination of: component A: one or more2,3-dihydroimidazo[1,2-c]quinazoline compounds of general formula (A1):

wherein X represents CR⁵R⁶ or NH; Y¹ represents CR³ or N; Chemical bondbetween

represents a single bond or double bond, with the proviso that when the

represents a double bond, Y² and Y³ independently represent CR⁴ or N,and when

represents a single bond, Y² and Y³ independently represent CR³R⁴ orNR⁴; Z¹, Z², Z³ and Z⁴ independently represent CH, CR² or N; R¹represents aryl optionally having 1 to 3 substituents selected from R¹¹,C₃₋₈ cycloalkyl optionally having 1 to 3 substituents selected from R¹¹,C₁₋₆ alkyl optionally substituted by aryl, heteroaryl, C₁₋₆ alkoxyaryl,aryloxy, heteroaryloxy or one or more halogen, C₁₋₆ alkoxy optionallysubstituted by carboxy, aryl, heteroaryl, C₁₋₆ alkoxyaryl, aryloxy,heteroaryloxy or one or more halogen, or a 3 to 15 membered mono- orbi-cyclic heterocyclic ring that is saturated or unsaturated, andcontains 1 to 3 heteroatoms selected from the group consisting of N, Oand S, and optionally having 1 to 3 substituents selected from R¹¹wherein R¹¹ represents halogen, nitro, hydroxy, cyano, carboxy, amino,N—(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,N—(C₁₋₆acyl)amino, N-(formyl)-N—(C₁₋₆alkyl)amino, N—(C₁₋₆alkanesulfonyl)amino, N-(carboxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino,N—(C₁₋₆alkoxycabonyl)amino, N—[N,N-di(C₁₋₆alkyl)amino methylene]amino,N—[N,N-di(C₁₋₆alkyl)amino (C₁₋₆ alkyl)methylene]amino,N—[N,N-di(C₁₋₆alkyl)amino C₂₋₆alkenyl]amino, aminocarbonyl,N—(C₁₋₆alkyl)aminocarbonyl, N,N-di(C₁₋₆alkyl)aminocarbonyl,C₃₋₈cycloalkyl, C₁₋₆ alkylthio, C₁₋₆alkanesulfonyl, sulfamoyl,C₁₋₆alkoxycarbonyl, N-arylamino wherein said aryl moiety is optionallyhaving 1 to 3 substituents selected from R¹⁰¹, N-(aryl C₁₋₆alkyl)aminowherein said aryl moiety is optionally having 1 to 3 substituentsselected from R¹⁰¹, aryl C₁₋₆alkoxycarbonyl wherein said aryl moiety isoptionally having 1 to 3 substituents selected from R¹⁰¹, C₁₋₆alkyloptionally substituted by mono-, di- or tri-halogen, amino,N—(C₁₋₆alkyl)amino or N,N-di(C₁₋₆alkyl)amino, C₁₋₆alkoxy optionallysubstituted by mono-, di- or tri-halogen, N—(C₁₋₆alkyl)sulfonamide, orN-(aryl)sulfonamide, or a 5 to 7 membered saturated or unsaturated ringhaving 1 to 3 heteroatoms selected from the group consisting of O, S andN, and optionally having 1 to 3 substituents selected from R¹⁰¹ whereinR¹⁰¹ represents halogen, carboxy, amino, N—(C₁₋₆ alkyl)amino,N,N-di(C₁₋₆alkyl)amino, aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl,N,N-di(C₁₋₆alkyl)aminocarbonyl, pyridyl, C₁₋₆ alkyl optionallysubstituted by cyano or mono- di- or tri-halogen, or C₁₋₆alkoxyoptionally substituted by cyano, carboxy, amino, N—(C₁₋₆ alkyl)amino,N,N-di(C₁₋₆alkyl)amino, aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl,N,N-di(C₁₋₆alkyl)aminocarbonyl or mono-, di- or tri-halogen; R²represents hydroxy, halogen, nitro, cyano, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)amino,N-(hydroxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino, C₁₋₆acyloxy, aminoC₁₋₆acyloxy,C₂₋₆alkenyl, aryl, a 5-7 membered saturated or unsaturated heterocyclicring having 1 to 3 heteroatoms selected from the group consisting O, Sand N, and optionally substituted by hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy,oxo, amino, amino C₁₋₆alkyl, N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,N—(C₁₋₆ acyl)amino, N—(C₁₋₆alkyl)carbonylamino, phenyl, phenyl C ₁₋₆alkyl, carboxy, C₁₋₆alkoxycarbonyl, aminocarbonyl,N—(C₁₋₆alkyl)aminocarbonyl, or N,N-di(C₁₋₆alkyl)amino, —C(O)—R²⁰ whereinR²⁰ represents C₁₋₆ alkyl, C₁₋₆ alkoxy, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, or a 5-7 membered saturatedor unsaturated heterocyclic ring having 1 to 3 heteroatoms selected fromthe group consisting O, S and N, and optionally substituted by C₁₋₆alkyl, C₁₋₆ alkoxy, oxo, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, phenyl, or benzyl, C₁₋₆alkyl optionally substituted by R²¹ or C₁₋₆ alkoxy optionallysubstituted by R²¹ wherein R²¹ represents cyano, mono-, di ortri-halogen, hydroxy, amino, N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,N-(hydroxyC₁₋₆ alkyl) amino, N-(halophenylC₁₋₆ alkyl) amino, amino C₂₋₆alkylenyl, C₁₋₆ alkoxy, hydroxyC₁₋₆ alkoxy, —C(O)—R²⁰¹, —NHC(O)—R²⁰¹,C₃₋₈cycloalkyl, isoindolino, phthalimidyl, 2-oxo-1,3-oxazolidinyl, arylor a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1to 4 heteroatoms selected from the group consisting O, S and Noptionally substituted by hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, hydroxyC₁₋₆ alkoxy, oxo, amino, aminoC₁₋₆alkyl,N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, orbenzyl, wherein R²⁰¹ represents hydroxy, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N-(halophenylC₁₋₆ alkyl) amino, C₁₋₆alkyl,aminoC₁₋₆ alkyl, aminoC₂₋₆ alkylenyl, C₁₋₆ alkoxy, a 5 or 6 memberedsaturated or unsaturated heterocyclic ring having 1 to 4 heteroatomsselected from the group consisting O, S and N optionally substituted byhydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, hydroxyC₁₋₆alkoxy, oxo, amino, N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆acyl)amino or benzyl; R³ represents hydrogen, halogen, aminocarbonyl, orC₁₋₆ alkyl optionally substituted by aryl C₁₋₆ alkoxy or mono-, di- ortri-halogen; R⁴ represents hydrogen or C₁₋₆ alkyl; R⁵ representshydrogen or C₁₋₆ alkyl; and R⁶ represents halogen, hydrogen or C₁₋₆alkyl; or a physiologically acceptable salt, solvate, hydrate orstereoisomer thereof; optionally in the form of a pharmaceuticalformulation which is ready for use to be administered simultaneously,concurrently, separately or sequentially; and component B: one or moresubstituted5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine compoundsof general formula (B):

wherein R¹ is hydrogen, chloro, methyl or methoxy, R² is hydrogen ormethoxy, with the proviso that at least one of R¹ and R² is other thanhydrogen, G¹ represents chloro, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxycarbonyl,5-membered aza-hetero-aryl, or the group —CH₂—OR³, —CH₂—NR⁴R⁵ or—C(═O)—NR⁴R⁶, wherein R³ is hydrogen, (C₁-C₄)-alkyl, (C₃-C₆)-cycloalkylor phenyl, (i) said (C₁-C₄)-alkyl is optionally substituted withhydroxy, (C₁-C₄)-alkoxy, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl, amino,aminocarbonyl, mono-(C₁-C₄)-alkylaminocarbonyl,di-(C₁-C₄)-alkylaminocarbonyl, (C₃-C₆)-cycloalkyl or up to three fluoroatoms,  and (ii) said (C₃-C₆)-cycloalkyl is optionally substituted withone or two substituents independently selected from the group consistingof (C₁-C₄)-alkyl, hydroxy and amino,  and (iii) said phenyl isoptionally substituted with one or two substituents independentlyselected from the group consisting of fluoro, chloro, bromo, cyano,trifluoromethyl, trifluoromethoxy, (C₁-C₄)-alkyl and (C₁-C₄)-alkoxy, R⁴is hydrogen or (C₁-C₄)-alkyl, R⁵ is hydrogen, (C₁-C₄)-alkyl,(C₁-C₄)-alkylcarbonyl, (C₃-C₆)-cycloalkyl or 4- to 6-memberedheterocycloalkyl, wherein (i) said (C₁-C₄)-alkyl is optionallysubstituted with hydroxy, (C₁-C₄)-alkoxy, hydroxycarbonyl,(C₁-C₄)-alkoxycarbonyl, aminocarbonyl, mono-(C₁-C₄)-alkylaminocarbonyl,di-(C₁-C₄)-alkylaminocarbonyl or (C₃-C₆)-cycloalkyl,  and (ii) said(C₃-C₆)-cycloalkyl is optionally substituted with one or twosubstituents independently selected from the group consisting of(C₁-C₄)-alkyl, hydroxy and amino,  and (iii) said 4- to 6-memberedheterocycloalkyl is optionally substituted with one or two substituentsindependently selected from the group consisting of (C₁-C₄)-alkyl,hydroxy, oxo and amino, R⁶ is hydrogen, (C₁-C₄)-alkyl,(C₃-C₆)-cycloalkyl or 4- to 6-membered hetero-cycloalkyl, wherein (i)said (C₁-C₄)-alkyl is optionally substituted with hydroxy,(C₁-C₄)-alkoxy, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl, amino,aminocarbonyl, mono-(C₁-C₄)-alkylaminocarbonyl,di-(C₁-C₄)-alkylaminocarbonyl or (C₃-C₆)-cycloalkyl,  and (ii) said(C₃-C₆)-cycloalkyl is optionally substituted with one or twosubstituents independently selected from the group consisting of(C₁-C₄)-alkyl, hydroxy and amino,  and (iii) said 4- to 6-memberedheterocycloalkyl is optionally substituted with one or two substituentsindependently selected from the group consisting of (C₁-C₄)-alkyl,hydroxy, oxo and amino,  or R⁴ and R⁵, or R⁴ and R⁶, respectively, arejoined and, taken together with the nitrogen atom to which they areattached, form a monocyclic, saturated 4- to 7-membered heterocycloalkylring which may contain a second ring heteroatom selected from N(R⁷) andO, and which may be substituted on ring carbon atoms with one or twosubstituents independently selected from the group consisting of(C₁-C₄)-alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein R⁷ ishydrogen, (C₁-C₄)-alkyl, formyl or (C₁-C₄)-alkylcarbonyl, and G²represents chloro, cyano, (C₁-C₄)-alkyl, or the group —CR^(8A)R^(8B)—OH,—CH₂—NR⁹R¹⁰, —C(═O)—NR¹¹R¹² or —CH₂—OR¹⁵, wherein R^(8A) and R^(8B) areindependently selected from the group consisting of hydrogen,(C₁-C₄)-alkyl, cyclopropyl and cyclobutyl, R⁹ is hydrogen or(C₁-C₄)-alkyl, R¹⁰ is hydrogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkylcarbonyl,(C₃-C₆)-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein (i)said (C₁-C₄)-alkyl is optionally substituted with hydroxy, amino,amino-carbonyl, mono-(C₁-C₄)-alkylaminocarbonyl or di-(C₁-C₄)-alkylamino-carbonyl,  and (ii) said (C₃-C₆)-cycloalkyl isoptionally substituted with one or two substituents independentlyselected from the group consisting of (C₁-C₄)-alkyl, hydroxy and amino, and (iii) said 4- to 6-membered heterocycloalkyl is optionallysubstituted with one or two substituents independently selected from thegroup consisting of (C₁-C₄)-alkyl, hydroxy, oxo and amino,  R¹¹ ishydrogen or (C₁-C₄)-alkyl, R¹² is hydrogen, (C₁-C₄)-alkyl,(C₃-C₆)-cycloalkyl or 4- to 6-membered hetero-cycloalkyl, wherein (i)said (C₁-C₄)-alkyl is optionally substituted with hydroxy, amino,amino-carbonyl, mono-(C₁-C₄)-alkylaminocarbonyl ordi-(C₁-C₄)-alkylamino-carbonyl, ′and (ii) said (C₃-C₆)-cycloalkyl isoptionally substituted with one or two substituents independentlyselected from the group consisting of (C₁-C₄)-alkyl, hydroxy and amino, and (iii) said 4- to 6-membered heterocycloalkyl is optionallysubstituted with one or two substituents independently selected from thegroup consisting of (C₁-C₄)-alkyl, hydroxy, oxo and amino,  or R⁹ andR¹⁰, or R¹¹ and R¹², respectively, are joined and, taken together withthe nitrogen atom to which they are attached, form a monocyclic,saturated 4- to 7-membered heterocycloalkyl ring which may contain asecond ring heteroatom selected from N(R¹³), O, S and S(O)₂, and whichmay be substituted on ring carbon atoms with up to three substituentsindependently selected from the group consisting of fluoro,(C₁-C₄)-alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein R¹³ ishydrogen, (C₁-C₄)-alkyl, (C₃-C₆)-cycloalkyl, formyl or(C₁-C₄)-alkylcarbonyl, and R¹⁵ is (C₁-C₄)-alkyl, with the proviso thatG¹ is not chloro when G² is chloro or cyano.
 2. The combinationaccording to claim 1, wherein: said component A is one or more2,3-dihydroimidazo[1,2-c]quinazoline compounds of general formula (A2)

in which: X represents CR⁵R⁶ or NH; Y¹ represents CR³ or N; the chemicalbond between

represents a single bond or double bond, with the proviso that when the

represents a double bond, Y² and Y³ independently represent CR⁴ or N,and when

represents a single bond, Y² and Y³ independently represent CR³R⁴ orNR⁴; Z¹, Z², Z³ and Z⁴ independently represent CH , CR² or N; R¹represents aryl optionally having 1 to 3 substituents selected from R¹¹,C₃₋₈ cycloalkyl optionally having 1 to 3 substituents selected from R¹¹,C₁₋₆ alkyl optionally substituted by aryl, heteroaryl, C₁₋₆ alkoxyaryl,aryloxy, heteroaryloxy or one or more halogen, C₁₋₆ alkoxy optionallysubstituted by carboxy, aryl, heteroaryl, C₁₋₆ alkoxyaryl, aryloxy,heteroaryloxy or one or more halogen, or a 3 to 15 membered mono- orbi-cyclic heterocyclic ring that is saturated or unsaturated, optionallyhaving 1 to 3 substituents selected from R¹¹, and contains 1 to 3heteroatoms selected from the group consisting of N, O and S, whereinR¹¹ represents halogen, nitro, hydroxy, cyano, carboxy, amino,N—(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,N—(C₁₋₆acyl)amino, N-(formyl)-N-(formyl)-N—(C₁₋₆alkyl)amino,N—(C₁₋₆alkanesulfonyl) amino, N-(carboxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino,N—(C₁₋₆alkoxycabonyl)amino, N—[N,N-di(C₁₋₆alkyl)amino methylene]amino,N—[N,N-di(C₁₋₆alkyl)amino (C₁₋₆alkyl)methylene]amino,N—[N,N-di(C₁₋₆alkyl)amino C₂₋₆alkenyl]amino, aminocarbonyl,N—(C₁₋₆alkyl)aminocarbonyl, N,N-di(C₁₋₆alkyl)aminocarbonyl,C₃₋₈cycloalkyl, C₁₋₆ alkylthio, C₁₋₆alkanesulfonyl, sulfamoyl,C₁₋₆alkoxycarbonyl, N-arylamino wherein said aryl moiety is optionallyhaving 1 to 3 substituents selected from R¹⁰¹, N-(aryl C₁₋₆alkyl)aminowherein said aryl moiety is optionally having 1 to 3 substituentsselected from R¹⁰¹, aryl C₁₋₆alkoxycarbonyl wherein said aryl moiety isoptionally having 1 to 3 substituents selected from R¹⁰¹, C₁₋₆alkyloptionally substituted by mono-, di- or tri-halogen, amino,N—(C₁₋₆alkyl)amino or N,N-di(C₁₋₆alkyl)amino, C₁₋₆alkoxy optionallysubstituted by mono-, di- or tri-halogen, N—(C₁₋₆alkyl)sulfonamide, orN-(aryl)sulfonamide, or a 5 to 7 membered saturated or unsaturated ringhaving 1 to 3 heteroatoms selected from the group consisting of O, S andN, and optionally having 1 to 3 substituents selected from R¹⁰¹ whereinR¹⁰¹ represents halogen, carboxy, amino, N—(C₁₋₆ alkyl)amino,N,N-di(C₁₋₆alkyl)amino, aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl,N,N-di(C₁₋₆alkyl)aminocarbonyl, pyridyl, C₁₋₆ alkyl optionallysubstituted by cyano or mono- di- or tri-halogen, and C₁₋₆alkoxyoptionally substituted by cyano, carboxy, amino, N—(C₁₋₆ alkyl)amino,N,N-di(C₁₋₆alkyl)amino, aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl,N,N-di(C₁₋₆alkyl)aminocarbonyl or mono-, di- or tri-halogen; R²represents hydroxy, halogen, nitro, cyano, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)amino,N-(hydroxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino, C₁₋₆ acyloxy, aminoC₁₋₆acyloxy,C₂₋₆alkenyl, aryl, a 5-7 membered saturated or unsaturated heterocyclicring having 1 to 3 heteroatoms selected from the group consisting O, Sand N, and optionally substituted by hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy,oxo, amino, amino C₁₋₆alkyl, N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,N—(C₁₋₆ acyl)amino, N—(C₁₋₆alkyl)carbonylamino, phenyl, phenyl C₁₋₆alkyl, carboxy, C₁₋₆alkoxycarbonyl, aminocarbonyl,N—C₁₋₆alkyl)aminocarbonyl, or N,N-di(C₁₋₆alkyl)amino, —C(O)—R²⁰ whereinR²⁰ represents C₁₋₆ alkyl, C₁₋₆ alkoxy, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, or a 5-7 membered saturatedor unsaturated heterocyclic ring having 1 to 3 heteroatoms selected fromthe group consisting O, S and N, and optionally substituted by C₁₋₆alkyl, C₁₋₆ alkoxy, oxo, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, phenyl, or benzyl, C₁₋₆alkyl optionally substituted by R²¹, or C₁₋₆ alkoxy optionallysubstituted by R²¹, wherein R²¹ represents cyano, mono-, di ortri-halogen, hydroxy, amino, N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,N-(hydroxyC₁₋₆ alkyl) amino, N-(halophenylC₁₋₆ alkyl) amino, amino C₂₋₆alkylenyl, C₁₋₆ alkoxy, hydroxyC₁₋₆ alkoxy, —C(O)—R²⁰¹, —NHC(O)—R²⁰¹,C₃₋₈cycloalkyl, isoindolino, phthalimidyl, 2-oxo-1,3-oxazolidinyl, arylor a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1to 4 heteroatoms selected from the group consisting O, S and N , andoptionally substituted by hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, hydroxyC₁₋₆ alkoxy, oxo, amino, aminoC₁₋₆alkyl,N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N—(C ₁₋₆ acyl)amino, orbenzyl,  wherein  R²⁰¹ represents hydroxy, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N-(halophenylC ₁₋₆ alkyl) amino, C₁₋₆alkyl,aminoC₁₋₆ alkyl, aminoC₂₋₆ alkylenyl, C₁₋₆ alkoxy, a 5 or 6 memberedsaturated or unsaturated heterocyclic ring having 1 to 4 heteroatomsselected from the group consisting O, S and N, and optionallysubstituted by hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl,hydroxyC₁₋₆ alkoxy, oxo, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino or benzyl; R³ representshydrogen, halogen, aminocarbonyl, or C₁₋₆ alkyl optionally substitutedby aryl C₁₋₆ alkoxy or mono-, di- or tri-halogen; R⁴ represents hydrogenor C₁₋₆ alkyl; R⁵ represents hydrogen or C₁₋₆ alkyl; and R⁶ representshalogen, hydrogen or C₁₋₆ alkyl; or a physiologically acceptable salt,solvate, hydrate or stereoisomer thereof; optionally in the form of apharmaceutical formulation which is ready for use to be administeredsimultaneously, concurrently, separately or sequentially.
 3. Thecombination according to claim 1, wherein: said component A is one ormore 2,3-dihydroimidazo[1,2-c]quinazoline compounds of general formula(A1) according to claim 1, which is selected from the list consisting ofspecific compound Examples 1-1 to 1-210 on pp. 47 to 106, specificcompound Examples 2-1 to 2-368 on pp. 107 to 204, specific compoundExamples 3-1 to 3-2 on pp. 205 to 207, and specific compound Examples4-1 to 4-2 on pp. 208 to 210, of in International patent applicationPCT/EP2003/010377, published as WO 04/029055 A1 on Apr. 8, 2004; or aphysiologically acceptable salt, solvate, hydrate or stereoisomerthereof; optionally in the form of a pharmaceutical formulation which isready for use to be administered simultaneously, concurrently,separately or sequentially.
 4. (canceled)
 4. (canceled)
 5. Thecombination according to claim 1, wherein said component A is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide.6. The combination according to claim 1, wherein said component A is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride.
 7. The combination according to claim 1, wherein saidcomponent B is4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-one.8. The combination according to claim 1, wherein said component A is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamideand said component B is4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-one.9. The combination according to claim 1, wherein said component A is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride and said component B is4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-one.10-13. (canceled)
 14. A method of treatment or prophylaxis of a cancerin a subject, comprising administering to said subject a therapeuticallyeffective amount of a combination according to claim
 1. 15. A kitcomprising a combination of: component A: one or more2,3-dihydroimidazo[1,2-c]quinazoline compounds of general formula (A1),or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, according to claim 1; component B: one or more substituted5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine compoundsof general formula (B), or a physiologically acceptable salt, solvate,hydrate or stereoisomer thereof, according to claim 1; in whichoptionally both or either of said components A and B are in the form ofa pharmaceutical formulation which is ready for use to be administeredsimultaneously, concurrently, separately or sequentially.
 16. The kitaccording to claim 15, wherein said component A is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamideand said component B is4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-one.17. The kit according to claim 15, wherein said component A is2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamidedihydrochloride and said component B is4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-one.18. A method for predicting the sensitivity and/or resistance of apatient with an endometrial cancer, to a combination of a component Aand a component B of claim 1, comprising identifying loss of tumorsuppressor PTEN or FBXW7, either alone or in combination with anotherform of PI3K pathway activation selected from perturbation of any of thefollowing alone or in combination: mutation in PIK3CA, PIK3CB, PIK3CD,PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3and/or FGFR4; PTEN loss and alteration of PIK3CA, PIK3CB, PIK3CD,PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3and/or FGFR4, which may be measured at either the protein level, mRNAlevel, or DNA level, thus providing rationale-based dosage as definedherein to overcome said resistance of said patient with endometrialcancer to a combination of a component A and a component B of claim 1.19. A method of determining the loss of tumor suppressor PTEN or FBXW7.20. A method for determining perturbations in PIK3CA, PIK3CB, PIK3CD,PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3and/or FGFR4, PTEN loss and alteration of PIK3CA, PIK3CB, PIK3CD,PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3and/or FGFR4.
 21. The combination according to claim 2, wherein: saidcomponent A is one or more 2,3-dihydroimidazo[1,2-c]quinazolinecompounds of general formula (A2) according to claim 2, which isselected from the list consisting of: Example 1:N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamideExample 2:N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamideExample 3:N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-2,4-dimethyl-1,3-thiazole-5-carboxamideExample 4:2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-thiazole-5-carboxamide.Example 5:2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]isonicotinamideExample 6:2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-methyl-1,3-thiazole-5-carboxamideExample 7:2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-propylpyrimidine-5-carboxamideExample 8:N-{8-[2-(4-ethylmorpholin-2-yl)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamideExample 9:N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamideExample 10:N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamideExample 11:N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamideExample 12:N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide1-oxide Example 13:2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide.Example 14:N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(2-pyrrolidin-1-ylethyl)nicotinamide.Example 15:6-(cyclopentylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamideExample Structure 16

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or a phsycologically acceptable salt, solvate, hydrate or stereosomerthereof; optionally in the form of a pharmaceutical formulation which isready for use to be administered simultaneously, concurrently,separately or sequentially.
 22. The combination according to claim 1,wherein: said component B is one or more substituted5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine compoundsof general formula (B) according to claim 1, which is selected from thelist consisting of: Example 14-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-oneExample 24-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-onedihydrochloride Example 3(3R)-3-({[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-onedihydrochloride Example 4(3R)-3-({[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-oneExample 54-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-oneExample 64-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo-[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-onedihydrochloride Example 7(3R)-3-({[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-onedihydrochloride Example 8(3R)-3-({[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-oneExample 9N²-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}glycinamidedihydrochloride Example 106-(Ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineExample 111-(4-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-1-yl)ethanonedihydrochloride Example 12[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methanolbis(formiate) Example 134-{[4-Amino-6-(hydroxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-oneExample 147-{[(3S)-3-Amino-3-methylpyrrolidin-1-yl]methyl}-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride Example 157-{[(3S)-3-Amino-3-methylpyrrolidin-1-yl]methyl}-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amineExample 161-(4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-1-yl)ethanonedihydrochloride Example 176-(Methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineformiate Example 186-(Ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineExample 196-(Ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminedihydrochloride Example 201-(4-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-1-yl)ethanoneExample 214-({4-Amino-6-[(2-hydroxyethoxy)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl}methyl)piperazin-2-oneformiate Example 222-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methoxy}ethanoldihydrochloride Example 236-(Butoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineformiate Example 245-(7-Methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)-6-(propoxy-methyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminebis(formiate) Example 256-[(Cyclopropylmethoxy)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminebis(formiate) Example 266-[(Cyclobutyloxy)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineExample 276-(Isopropoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-yl-methyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineformiate Example 286-[(2-Methoxyethoxy)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineformiate Example 295-(7-Methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)-6-[(2,2,2-trifluoroethoxy)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-amineformiate Example 306-[(2-Aminoethoxy)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride Example 31 Methyl{[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-yl-methyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methoxy}acetateExample 32{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methoxy}aceticacid Example 332-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methoxy}acetamideExample 342-({7-[(4-Acetylpiperazin-1-yl)methyl]-4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl}methoxy)acetamideExample 355-(7-Methoxy-5-methyl-1-benzothiophen-2-yl)-6-(phenoxymethyl)-7-(piperazin-1-yl-methyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminebis(formiate) Example 365-(7-Methoxy-5-methyl-1-benzothiophen-2-yl)-6-[(methylamino)methyl]-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride Example 376-[(Dimethylamino)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride Example 386-[(Ethylamino)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride Example 392-({[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}amino)ethanoltrihydrochloride Example 40rac-1-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperidin-3-oltrihydrochloride Example 411-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperidin-4-oltrihydrochloride Example 42rac-1-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}pyrrolidin-3-oltrihydrochloride Example 436-[(Diethylamino)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride Example 446-[(Cyclobutylamino)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride Example 455-(7-Methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)-6-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride Example 466-[(Cyclopropylamino)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride Example 476-({[(Cyclopropylmethyl)amino]methyl}-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride Example 48N-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}glycinetrihydrochloride Example 494-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperazin-2-onetrihydrochloride Example 50[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methanolExample 51(3S)-3-({[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}amino)pyrrolidin-2-oneExample 524-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperazin-2-oneExample 53rac-1-({[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}amino)propan-2-olExample 541-({[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}amino)-2-methylpropan-2-olExample 551-(4-{[4-Amino-6-(hydroxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-1-yl)ethanoneExample 56(3R)-3-[({7-[(4-Acetylpiperazin-1-yl)methyl]-4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl}methyl)amino]pyrrolidin-2-oneExample 571-(4-{[4-Amino-6-({[(2-hydroxy-2-methylpropyl)amino]methyl}-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-1-yl)ethanoneExample 584-({4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-6-[(3-oxopiperazin-1-yl)-methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}methyl)piperazine-1-carbaldehydeformiate Example 594-({7-[(4-Acetylpiperazin-1-yl)methyl]-4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl}methyl)piperazin-2-oneExample 60 Methyl4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylcarbonyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylatebis(formiate) Example 615-(7-Methoxy-5-methyl-1-benzothiophen-2-yl)-6-(1,3-oxazol-5-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride Example 626-(Aminomethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride Example 63N-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}acetamidebis(trifluoroacetate) Example 64N-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}acetamidedihydrochloride Example 65N-({4-Amino-7-[(4-formylpiperazin-1-yl)methyl]-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl}methyl)acetamideformiate Example 66N-({7-[(4-Acetylpiperazin-1-yl)methyl]-4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl}methyl)acetamideExample 67N-({4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl}methyl)acetamideExample 684-Amino-6-(hydroxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carbonitrileExample 694-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carbonitrileExample 704-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carbonitrileExample 714-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-6-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazine-7-carbonitrileExample 72N,N′-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazine-6,7-diyl]bis(methylene)}diacetamideExample 732-[4-Amino-6-(hydroxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]propan-2-olExample 744-{[4-Amino-7-(2-hydroxypropan-2-yl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperazin-2-oneExample 75[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]methanolExample 764-{[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperazin-2-oneExample 771-({[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}amino)-2-methylpropan-2-olformiate Example 781-({[4-Amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}amino)-2-methylpropan-2-olExample 79[4-Amino-7-chloro-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methanolExample 804-{[4-Amino-7-chloro-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperazin-2-oneExample 811-({[4-Amino-7-chloro-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}amino)-2-methylpropan-2-olformiate Example 821-({[4-Amino-7-chloro-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}amino)-2-methylpropan-2-olExample 837-Chloro-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amineExample 845-(7-Methoxy-5-methyl-1-benzothiophen-2-yl)-6-methyl-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineformiate Example 856-Chloro-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminetrihydrochloride Example 86[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methanolExample 871-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}imidazolidin-2-oneExample 884-{[4-Amino-5-(7-methoxy-1-benzothiophen-2-yl)-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-oneExample 894-{[4-Amino-6-(methoxymethyl)-5-(5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-oneExample 901-[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]ethanolExample 91[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl](cyclopropyl)methanolExample 92(3S)-3-({[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-oneExample 93(3S)-3-({[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-oneExample No. Structure  94

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Example 1064-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-N-[(3R)-2-oxopyrrolidin-3-yl]-pyrrolo[2,1-f][1,2,4]triazine-7-carboxamideExample 1074-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]carbonyl}piperazin-2-oneExample No. Structure 108

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Example 1244-{[4-Amino-5-(5,7-dimethoxy-1-benzothiophen-2-yl)-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-oneExample 1254-{[4-Amino-7-(hydroxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperazin-2-oneExample 1264-{[4-Amino-7-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperazin-2-oneExample 1274-{[4-Amino-7-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl}piperazin-2-oneor a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof; optionally in the form of a pharmaceutical formulation which isready for use to be administered simultaneously, concurrently,separately or sequentially.
 23. The method according to claim 14,wherein said cancer is endometrial cancer.
 24. The method according toclaim 15, wherein said endometrial cancer is selected from the groupconsisting of 1st line, 2nd line, relapsed, refractory, type I or typeII endometrial cancer, and endometriosis.
 25. The method according toclaim 14, wherein said cancer is 1st line, 2nd line, relapsed,refractory, or type I endometrial cancer.
 26. The method according toclaim 14, wherein said cancer is 1st line, 2nd line, relapsed,refractory, type II endometrial cancer, or endometriosis.
 27. The methodaccording to claim 18, wherein said endometrial cancer is selected fromthe group consisting of 1st line, 2nd line, relapsed, refractory, type Ior type II endometrial cancer, and endometriosis.